Tricyclic urea compounds as jak2 v617f inhibitors

ABSTRACT

The present application provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.

TECHNICAL FIELD

The present invention provides tricyclic urea compounds that modulatethe activity of the V617F variant of JAK2 and are useful in thetreatment of diseases related to the V617F variant of JAK2, includingcancer.

BACKGROUND

Janus kinase (JAK) 2 plays pivotal roles in signaling by severalcytokine receptors. The mutant JAK2 V617F is the most common molecularevent associated with myeloproliferative neoplasms. Selective targetingof the JAK2 V617F mutant may be useful for treating various pathologies,while sparing essential JAK2 functions. This application is directed tothis need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula F

or pharmaceutically acceptable salts thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting an activityof the V617F variant of JAK2 kinase comprising contacting the kinasewith a compound of Formula I, or a pharmaceutically acceptable saltthereof.

The present invention further provides methods of treating a disease ora disorder associated with expression or activity of the V617F variantof JAK2 kinase in a patient by administering to a patient atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula I, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula I,or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION

The present application provides compounds of Formula F

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(M)substituents;

R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)R^(b21), NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), and OS(O)₂R^(b21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(b21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b21) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2B)substituents;

each R^(e21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(2B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22),C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)R^(b22), NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), and OS(O)₂R^(b22), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2C) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(c22) andR^(d22) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2C) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2C)substituents;

each R^(b22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b22) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2C)substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(2C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a23), SR^(a23),NHOR^(a23), C(O)R^(b23), C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)),C(O)OR^(a23), OC(O)R^(b23), OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)NR^(c23)R^(d23), NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23),NR^(c23)C(O)NR^(c23)R^(d23), C(═NR^(e23))R^(b23),C(═NR^(e23))NR^(c23)R^(d23), NR^(c23)C(═NR^(e23))NR^(c23)R^(d23),NR^(c23)C(═NR^(e23))R^(b23), NR^(c23)S(O)R^(b23),NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)(═NR^(e23))R^(b23), NR^(c23)S(O)₂NR^(c23)R^(d23),S(O)R^(b23), S(O)NR^(c23)R^(d23), S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23),OS(O)(═NR^(e23))R^(b23), and OS(O)₂R^(b23), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a23), R^(c23) and R^(d23) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c23) and R^(d23) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b23) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e23) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R³ and R^(3′) are each independently selected from H, D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a3), SR^(a3), NHOR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))R^(b3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)NR^(c3)R^(d3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)(═NR^(e3))R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), OS(O)(═NR^(e3))R^(b3), and OS(O)₂R^(b3), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R³ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(3A) substituents;

or, R³ and R^(3′) attached to the same C atom, together with the C atomto which they are attached, form a 3-10 membered cycloalkyl or a 4-10membered heterocycloalkyl group, wherein the 3-10 membered cycloalkyl or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected R^(3A) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a3), R^(c3) and R^(d3) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3A) substituents;

or, any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

each R^(b3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b3) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3A)substituents;

each R^(e3) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a31), SR^(a31), NHOR^(a31), C(O)R^(b31),C(O)NR^(c31)R^(d31), C(O)NR^(c31)(OR^(a31)), C(O)OR^(a31), OC(O)R^(b31),OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c31)NR^(c31)R^(d31),NR^(c31)C(O)R^(b31), NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31),C(═NR^(e31))R^(b31), C(═NR^(e31))NR^(c31)R^(d31),NR^(c31)C(═NR^(e31))NR^(c31)R^(d31), NR^(c31)C(═NR^(e31))R^(b31),NR^(c31)S(O)R^(b31), NR^(c31)S(O)NR^(c31)R^(d31), NR^(c31)S(O)₂R^(b31),NR^(c31)S(O)(═NR^(e31))R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31),S(O)R^(b31), S(O)NR^(c31)R^(d31), S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31),OS(O)(═NR^(e31))R^(b31), and OS(O)₂R^(b31), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3B) substituents;

each R^(a31), R^(c31), and R^(d31) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a31), R^(c31) andR^(d31) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3B) substituents;

or, any R^(c31) and R^(d31) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3B)substituents;

each R^(b31) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b31) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3B)substituents;

each R^(e31) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a32), SR^(a32), NHOR^(a32), C(O)R^(b32),C(O)NR^(c32)R^(d32), C(O)NR^(c32)(OR^(a32)), C(O)OR^(a32), OC(O)R^(b32),OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)NR^(c32)R^(d32),NR^(c32)C(O)R^(b32), NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32),C(═NR^(e32))R^(b32), C(═NR^(e32))NR^(c32)R^(d32),NR^(c32)C(═NR^(e32))NR^(c32)R^(d32), NR^(c32)C(═NR^(e32))R^(b32),NR^(c32)S(O)R^(b32), NR^(c32)S(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)(═NR^(e32))R^(b32), NR^(c32)S(O)₂NR^(c32)R^(d32),S(O)R^(b32), S(O)NR^(c32)R^(d32), S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32),OS(O)(═NR^(e32))R^(b32), and OS(O)₂R^(b32), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3C) substituents;

each R^(a32), R^(c32), and R^(d32) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a32), R^(c32) andR^(d32) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3C) substituents;

or, any R^(c32) and R^(d32) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3C)substituents;

each R^(b32) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b32) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3C)substituents;

each R^(e32) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a33), SR^(a33),NHOR^(a33), C(O)R^(b33), C(O)NR^(c33)R^(d33), C(O)NR^(c33)(OR^(a33)),C(O)OR^(a33), OC(O)R^(b33), OC(O)NR^(c33)R^(d33), NR^(c33)R^(d33),NR^(c33)NR^(c33)R^(d33), NR^(c33)C(O)R^(b33), NR^(c33)C(O)OR^(a33),NR^(c33)C(O)NR^(c33)R^(d33), C(═NR^(e33))R^(b33),C(═NR^(e33))NR^(c33)R^(d33), NR^(c33)C(═NR^(e33))NR^(c33)R^(d33),NR^(c33)C(═NR^(e33))R^(b33), NR^(c33)S(O)R^(b33),NR^(c33)S(O)NR^(c33)R^(d33), NR^(c33)S(O)₂R^(b33),NR^(c33)S(O)(═NR^(e33))R^(b33), NR^(c33)S(O)₂NR^(c33)R^(d33),S(O)R^(b33), S(O)NR^(c33)R^(d33), S(O)₂R^(b33), S(O)₂NR^(c33)R^(d33),OS(O)(═NR^(e33))R^(b33), and OS(O)₂R^(b33), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(3C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a33), R^(c33), and R^(d33) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a33), R^(c33) and R^(d33) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c33) and R^(d33) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b33) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b33) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e33) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), and OS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4A) substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4A) substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(b4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b4) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4A)substituents;

each R^(e4) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), and OS(O)₂R^(b41), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b41) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4B)substituents;

each R^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42)NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))R^(b42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), and OS(O)₂R^(b42), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(c42) andR^(d42) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4C) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4C)substituents;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b42) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4C)substituents;

each R^(e42) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a43), SR^(a43),NHOR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)),C(O)OR^(a43), OC(O)R^(b43), OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43),NR^(c43)NR^(c43)R^(d43), NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43),NR^(c43)C(O)NR^(c43)R^(d43), C(═NR^(e43))R^(b43),C(═NR^(e43))NR^(c43)R^(d43), NR^(c43)C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))R^(b43), NR^(c43)S(O)R^(b43),NR^(c43)S(O)NR^(c43)R^(d43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)(═NR^(e43))R^(b43), NR^(c43)S(O)₂NR^(c43)R^(d43),S(O)R^(b43), S(O)NR^(c43)R^(d43), S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43),OS(O)(═NR^(e43))R^(b43), and OS(O)₂R^(b43), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a43), R^(c43), and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a43), R^(c43) and R^(d43) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c43) and R^(d43) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b43) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b43) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e43) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R⁵ is selected from H, D, halo, C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a5), SR^(a5),NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)NR^(c5)(OR^(a5)),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))R^(b5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)(═NR^(e5))R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5),OS(O)(═NR^(e5))R^(b5), and OS(O)₂R^(b5), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5A) substituents;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a5), R^(c5) and R^(d5) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5A) substituents;

or, any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

each R^(b5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b5) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5A)substituents;

each R^(e5) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),C(═NR^(e51))R^(b51), C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))R^(b51),NR^(c51)S(O)R^(b51), NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b51), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), and OS(O)₂R^(b51), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a51), R^(c51) andR^(d51) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(b51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b51) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5B)substituents;

each R^(e51) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)R^(b52), NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(e52))R^(b52), and OS(O)₂R^(b52), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a52), R^(c52) andR^(d52) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5C) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5C)substituents;

each R^(b52) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b52) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5C)substituents;

each R^(e52) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a53), SR^(a53),NHOR^(a53), C(O)R^(b53), C(O)NR^(c53)R^(d53), C(O)NR^(c53)(OR^(a53)),C(O)OR^(a53), OC(O)R^(b53), OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53),NR^(c53)NR^(c53)R^(d53), NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53),NR^(c53)C(O)NR^(c53)R^(d53), C(═NR^(e53))R^(b53),C(═NR^(e53))NR^(c53)R^(d53), NR^(c53)C(═NR^(e53))NR^(c53)R^(d53),NR^(c53)C(═NR^(e53))R^(b53), NR^(c53)S(O)R^(b53),NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)(═NR^(e53))R^(b53), NR^(c53)S(O)₂NR^(c53)R^(d53),S(O)R^(b53), S(O)NR^(c53)R^(d53), S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53),OS(O)(═NR^(e53))R^(b53), and OS(O)₂R^(b53), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a53), R^(c53), and R^(d53) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a53), R^(c53) and R^(d53) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c53) and R^(d53) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b53) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b53) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e53) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; and

each R^(M) is independently selected from H, D, OH, halo, oxo, CN,C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-.

In some embodiments:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(M)substituents;

R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2A)substituents;

each R^(2A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21).NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)R^(b21), NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), and OS(O)₂R^(b21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(b21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b21) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2B)substituents;

each R^(e21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(2B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22),C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)R^(b22), NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), and OS(O)₂R^(b22), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2C) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(c22) andR^(d22) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2C) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2C)substituents;

each R^(b22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b22) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(2C)substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(2C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a23), SR^(a23),NHOR^(a23), C(O)R^(b23), C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)),C(O)OR^(a23), OC(O)R^(b23), OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)NR^(c23)R^(d23), NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23),NR^(c23)C(O)NR^(c23)R^(d23), C(═NR^(e23))R^(b23),C(═NR^(e23))NR^(c23)R^(d23), NR^(c23)C(═NR^(e23))NR^(c23)R^(d23),NR^(c23)C(═NR^(e23))R^(b23), NR^(c23)S(O)R^(b23),NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)(═NR^(e23))R^(b23), NR^(c23)S(O)₂NR^(c23)R^(d23),S(O)R^(b23), S(O)NR^(c23)R^(d23), S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23),OS(O)(═NR^(e23))R^(b23), and OS(O)₂R^(b23), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a23), R^(c23) and R^(d23) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c23) and R^(d23) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b23) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e23) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R³ and R^(3′) are each independently selected from H, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a3), SR^(a3), NHOR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))R^(b3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)NR^(c3)R^(d3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)(═NR^(e3))R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),S(O)₂NR^(c3)R^(d3), OS(O)(═NR^(e3))R^(b3), and OS(O)₂R^(b3), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R³ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(3A) substituents;

or, R³ and R^(3′) attached to the same C atom, together with the C atomto which they are attached, form a 3-10 membered cycloalkyl or a 4-10membered heterocycloalkyl group, wherein the 3-10 membered cycloalkyl or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, 4, 5, 6, 7, or 8 independently selected R^(3A) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a3), R^(c3) and R^(d3) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3A) substituents;

or, any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

each R^(b3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b3) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3A)substituents;

each R^(e3) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a31), SR^(a31), NHOR^(a31), C(O)R^(b31),C(O)NR^(c31)R^(d31), C(O)NR^(c31)(OR^(a31)), C(O)OR^(a31), OC(O)R^(b31),OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c31)NR^(c31)R^(d31),NR^(c31)C(O)R^(b31), NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31),C(═NR^(e31))R^(b31), C(═NR^(e31))NR^(c31)R^(d31),NR^(c31)C(═NR^(e31))NR^(c31)R^(d31), NR^(c31)C(═NR^(e31))R^(b31),NR^(c31)S(O)R^(b31), NR^(c31)S(O)NR^(c31)R^(d31), NR^(c31)S(O)₂R^(b31),NR^(c31)S(O)(═NR^(e31))R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31),S(O)R^(b31), S(O)NR^(c31)R^(d31), S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31),OS(O)(═NR^(e31))R^(b31), and OS(O)₂R^(b31), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3B) substituents;

each R^(a31), R^(c31), and R^(d31) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a31), R^(c31) andR^(d31) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3B) substituents;

or, any R^(c31) and R^(d31) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3B)substituents;

each R^(b31) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b31) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3B)substituents;

each R^(e31) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a32), SR^(a32), NHOR^(a32), C(O)R^(b32),C(O)NR^(c32)R^(d32), C(O)NR^(c32)(OR^(a32)), C(O)OR^(a32), OC(O)R^(b32),OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)NR^(c32)R^(d32),NR^(c32)C(O)R^(b32), NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32),C(═NR^(e32))R^(b32), C(═NR^(e32))NR^(c32)R^(d32),NR^(c32)C(═NR^(e32))NR^(c32)R^(d32), NR^(c32)C(═NR^(e32))R^(b32),NR^(c32)S(O)R^(b32), NR^(c32)S(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)(═NR^(e32))R^(b32), NR^(c32)S(O)₂NR^(c32)R^(d32),S(O)R^(b32), S(O)NR^(c32)R^(d32), S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32),OS(O)(═NR^(e32))R^(b32), and OS(O)₂R^(b32), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3C) substituents;

each R^(a32), R^(c32), and R^(d32) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a32), R^(c32) andR^(d32) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3C) substituents;

or, any R^(c32) and R^(d32) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3C)substituents;

each R^(b32) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b32) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(3C)substituents;

each R^(e32) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(3C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a33), SR^(a33),NHOR^(a33), C(O)R^(b33), C(O)NR^(c33)R^(d33), C(O)NR^(c33)(OR^(a33)),C(O)OR^(a33), OC(O)R^(b33), OC(O)NR^(c33)R^(d33), NR^(c33)R^(d33),NR^(c33)NR^(c33)R^(d33), NR^(c33)C(O)R^(b33), NR^(c33)C(O)OR^(a33),NR^(c33)C(O)NR^(c33)R^(d33), C(═NR^(e33))R^(b33),C(═NR^(e33))NR^(c33)R^(d33), NR^(c33)C(═NR^(e33))NR^(c33)R^(d33),NR^(c33)C(═NR^(e33))R^(b33), NR^(c33)S(O)R^(b33),NR^(c33)S(O)NR^(c33)R^(d33), NR^(c33)S(O)₂R^(b33),NR^(c33)S(O)(═NR^(e33))R^(b33), NR^(c33)S(O)₂NR^(c33)R^(d33),S(O)R^(b33), S(O)NR^(c33)R^(d33), S(O)₂R^(b33), S(O)₂NR^(c33)R^(d33),OS(O)(═NR^(e33))R^(b33), and OS(O)₂R^(b33), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(3C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a33), R^(c33), and R^(d33) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a33), R^(c33) and R^(d33) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c33) and R^(d33) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b33) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b33) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e33) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)NR^(c4)R^(d4). NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))R^(b4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)(═NR^(e4))R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4),OS(O)(═NR^(e4))R^(b4), and OS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4A) substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4A) substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(b4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b4) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4A)substituents;

each R^(e4) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a41), SR^(a41), NHOR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), and OS(O)₂R^(b41), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b41) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4B)substituents;

each R^(e41) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42)NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))R^(b42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), and OS(O)₂R^(b42), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(c42) andR^(d42) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4C) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4C)substituents;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b42) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(4C)substituents;

each R^(e42) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(4C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a43), SR^(a43),NHOR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)),C(O)OR^(a43), OC(O)R^(b43), OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43),NR^(c43)NR^(c43)R^(d43), NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43),NR^(c43)C(O)NR^(c43)R^(d43), C(═NR^(e43))R^(b43),C(═NR^(e43))NR^(c43)R^(d43), NR^(c43)C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))R^(b43), NR^(c43)S(O)R^(b43),NR^(c43)S(O)NR^(c43)R^(d43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)(═NR^(e43))R^(b43), NR^(c43)S(O)₂NR^(c43)R^(d43),S(O)R^(b43), S(O)NR^(c43)R^(d43), S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43),OS(O)(═NR^(e43))R^(b43), and OS(O)₂R^(b43), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a43), R^(c43), and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a43), R^(c43) and R^(d43) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c43) and R^(d43) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b43) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b43) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e43) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R⁵ is selected from H, halo, C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a5), SR^(a5),NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)NR^(c5)(OR^(a5)),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))R^(b5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)(═NR^(e5))R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5),OS(O)(═NR^(e5))R^(b5), and OS(O)₂R^(b5), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5A) substituents;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a5), R^(c5) and R^(d5) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5A) substituents;

or, any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

each R^(b5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b5) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5A)substituents;

each R^(e5) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a51), SR^(a51), NHOR^(a51), C(O)R^(b51),C(O)NR^(c51)R^(d51), C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),C(═NR^(e51))R^(b51), C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))R^(b51),NR^(c51)S(O)R^(b51), NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b51), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), and OS(O)₂R^(b51), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a51), R^(c51) andR^(d51) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(b51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b51) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5B)substituents;

each R^(e51) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)R^(b52), NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(e52))R^(b52), and OS(O)₂R^(b52), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a52), R^(c52) andR^(d52) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5C) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5C)substituents;

each R^(b52) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b52) are each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(5C)substituents;

each R^(e52) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

each R^(5C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a53), SR^(a53),NHOR^(a53), C(O)R^(b53), C(O)NR^(c53)R^(d53), C(O)NR^(c53)(OR^(a53)),C(O)OR^(a53), OC(O)R^(b53), OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53),NR^(c53)NR^(c53)R^(d53), NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53),NR^(c53)C(O)NR^(c53)R^(d53), C(═NR^(e53))R^(b53),C(═NR^(e53))NR^(c53)R^(d53), NR^(c53)C(═NR^(e53))NR^(c53)R^(d53),NR^(c53)C(═NR^(e53))R^(b53), NR^(c53)S(O)R^(b53),NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)(═NR^(e53))R^(b53), NR^(c53)S(O)₂NR^(c53)R^(d53),S(O)R^(b53), S(O)NR^(c53)R^(d53), S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53),OS(O)(═NR^(e53))R^(b53), and OS(O)₂R^(b53), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents;

each R^(a53), R^(c53), and R^(d53) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a53), R^(c53) and R^(d53) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents;

or, any R^(c53) and R^(d53) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5-6 memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(b53) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b53) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(M)substituents;

each R^(e53) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; and

each R^(M) is independently selected from H, OH, halo, oxo, CN, C(O)OH,NH₂, NO₂, SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21), and OS(O)₂R^(b21), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(b21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b21) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents;

each R^(2B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)C(O)R^(b22),NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)₂R^(b22)NR^(c22)S(O)₂NR^(c22)R^(d22), S(O)R^(b22), S(O)NR^(c22)R^(d22),S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22), and OS(O)₂R^(b22), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2C) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(c22) andR^(d22) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2C) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2C)substituents;

each R^(b22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b22) are each optionally substitutedwith 1, 2, 3, or 4, independently selected R^(2C) substituents;

each R^(2C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a23), SR^(a23),C(O)R^(b23), C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)), C(O)OR^(a23),OC(O)R^(b23), OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23), NR^(c23)C(O)NR^(c23)R^(d23),NR^(c23)S(O)R^(b23), NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)₂NR^(c23)R^(d23), S(O)R^(b23), S(O)NR^(c23)R^(d23),S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23), and OS(O)₂R^(b23);

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c23) and R^(d23) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R³ and R^(3′) are each independently selected from H, D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)NR^(c3)R^(d3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3), and OS(O)₂R^(b3),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R³ are each optionally substituted with 1, 2, 3, or 4independently selected R^(3A) substituents;

or, R³ and R^(3′) attached to the same C atom, together with the C atomto which they are attached, form a 3-10 membered cycloalkyl or a 4-10membered heterocycloalkyl group, wherein the 3-10 membered cycloalkyl or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(3A) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a3), R^(c3) and R^(d3) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

or, any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

each R^(b3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b3) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3A) substituents;

each R^(3A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a31), SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),C(O)NR^(c31)(OR^(a31)), C(O)OR^(a31), OC(O)R^(b31),OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c31)C(O)R^(b31),NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31), NR^(c31)S(O)R^(b31),NR^(c31)S(O)NR^(c31)R^(d31), NR^(c31)S(O)₂R^(b31),NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31), S(O)NR^(c31)R^(d31),S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31), and OS(O)₂R^(b31), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(3B) substituents;

each R^(a31), R^(c31), and R^(d31) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a31), R^(c31) andR^(d31) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3B) substituents;

or, any R^(c31) and R^(d31) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3B)substituents;

each R^(b31) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b31) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3B) substituents;

each R^(3B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a32), SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32),C(O)NR^(c32)(OR^(a32)), C(O)OR^(a32), OC(O)R^(b32),OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)C(O)R^(b32),NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32), NR^(c32)S(O)R^(b32),NR^(c32)S(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)R^(b32), S(O)NR^(c32)R^(d32),S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32), and OS(O)₂R^(b32), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(3C) substituents;

each R^(a32), R^(c32), and R^(d32) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a32), R^(c32) andR^(d32) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3C) substituents;

or, any R^(c32) and R^(d32) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3C)substituents;

each R^(b32) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b32) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3C) substituents;

each R^(3C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a33), SR^(a33),C(O)R^(b33), C(O)NR^(c33)R^(d33), C(O)NR^(c33)(OR^(a33)), C(O)OR^(a33),OC(O)R^(b33), OC(O)NR^(c33)R^(d33), NR^(c33)R^(d33),NR^(c33)C(O)R^(b33), NR^(c33)C(O)OR^(a33), NR^(c33)C(O)NR^(c33)R^(d33),NR^(c33)S(O)R^(b33), NR^(c33)S(O)NR^(c33)R^(d33), NR^(c33)S(O)₂R^(b33),NR^(c33)S(O)₂NR^(c33)R^(d33), S(O)R^(b33), S(O)NR^(c33)R^(d33),S(O)₂R^(b33), S(O)₂NR^(c33)R^(d33), and OS(O)₂R^(b33);

each R^(a33), R^(c33), and R^(d33) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c33) and R^(d33) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b33) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), andOS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(b4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b4) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a41), SR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)R^(b41), S(O)NR^(c41)R^(d41),S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41), and OS(O)₂R^(b41), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b41) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(4B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)R^(b42),NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)R^(b42), S(O)NR^(c42)R^(d42),S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42), and OS(O)₂R^(b42), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(c42) andR^(d42) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4C) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4C)substituents;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b42) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(4C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a43), SR^(a43),C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43),OC(O)R^(b43), OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43),NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43), NR^(c43)C(O)NR^(c43)R^(d43),NR^(c43)S(O)R^(b43), NR^(c43)S(O)NR^(c43)R^(d43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)₂NR^(c43)R^(d43), S(O)R^(b43), S(O)NR^(c43)R^(d43),S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43), and OS(O)₂R^(b43);

each R^(a43), R^(c43), and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c43) and R^(d43) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b43) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R⁵ is selected from H, D, halo, C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5), andOS(O)₂R^(b5), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are each optionally substituted with1,2, 3, or 4 independently selected R^(5A) substituents;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a5), R^(c5) and R^(d5) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

or, any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

each R^(b5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b5) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(5A) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a51), SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51),NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51),NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51), S(O)NR^(c51)R^(d51),S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51), and OS(O)₂R^(b51), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a51), R^(c51) andR^(d51) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(b51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b51) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a52), SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)C(O)R^(b52),NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52),NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52), S(O)NR^(c52)R^(d52),S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52), and OS(O)₂R^(b52), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a52), R^(c52) andR^(d52) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5C) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5C)substituents;

each R^(b52) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b52) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5C) substituents;

each R^(5C) is independently selected from D, halo, oxo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a53), SR^(a53),C(O)R^(b53), C(O)NR^(c53)R^(d53), C(O)NR^(c53)(OR^(a53)), C(O)OR^(a53),OC(O)R^(b53), OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53),NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53), NR^(c53)C(O)NR^(c53)R^(d53),NR^(c53)S(O)R^(b53), NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)₂NR^(c53)R^(d53), S(O)R^(b53), S(O)NR^(c53)R^(d53),S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53), and OS(O)₂R^(b53);

each R^(a53), R^(c53), and R^(d53) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c53) and R^(d53) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group; and

each R^(b53) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-;

R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)C(O)R^(b21),NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21), and OS(O)₂R^(b21), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(b21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b21) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents;

each R^(2B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)C(O)R^(b22),NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)₂R^(b22)NR^(c22)S(O)₂NR^(c22)R^(d22), S(O)R^(b22), S(O)NR^(c22)R^(d22),S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22), and OS(O)₂R^(b22), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2C) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(c22) andR^(d22) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2C) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2C)substituents;

each R^(b22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b22) are each optionally substitutedwith 1, 2, 3, or 4, independently selected R^(2C) substituents;

each R^(2C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a23), SR^(a23),C(O)R^(b23), C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)), C(O)OR^(a23),OC(O)R^(b23), OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23), NR^(c23)C(O)NR^(c23)R^(d23),NR^(c23)S(O)R^(b23), NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)₂NR^(c23)R^(d23), S(O)R^(b23), S(O)NR^(c23)R^(d23),S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23), and OS(O)₂R^(b23);

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c23) and R^(d23) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R³ and R^(3′) are each independently selected from H, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)NR^(c3)R^(d3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3), and OS(O)₂R^(b3),wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R³ are each optionally substituted with 1, 2, 3, or 4independently selected R^(3A) substituents;

or, R³ and R^(3′) attached to the same C atom, together with the C atomto which they are attached, form a 3-10 membered cycloalkyl or a 4-10membered heterocycloalkyl group, wherein the 3-10 membered cycloalkyl or4-10 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(3A) substituents;

each R^(a3), R^(c3), and R^(d3) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a3), R^(c3) and R^(d3) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

or, any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents;

each R^(b3) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b3) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3A) substituents;

each R^(3A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a31), SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),C(O)NR^(c31)(OR^(a31)), C(O)OR^(a31), OC(O)R^(b31),OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c31)C(O)R^(b31),NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31), NR^(c31)S(O)R^(b31),NR^(c31)S(O)NR^(c31)R^(d31), NR^(c31)S(O)₂R^(b31),NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31), S(O)NR^(c31)R^(d31),S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31), and OS(O)₂R^(b31), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(3B) substituents;

each R^(a31), R^(c31), and R^(d31) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a31), R^(c31) andR^(d31) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3B) substituents;

or, any R^(c31) and R^(d31) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3B)substituents;

each R^(b31) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b31) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3B) substituents;

each R^(3B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a32), SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32),C(O)NR^(c32)(OR^(a32)), C(O)OR^(a32), OC(O)R^(b32),OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)C(O)R^(b32),NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32), NR^(c32)S(O)R^(b32),NR^(c32)S(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)R^(b32), S(O)NR^(c32)R^(d32),S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32), and OS(O)₂R^(b32), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(3C) substituents;

each R^(a32), R^(c32), and R^(d32) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a32), R^(c32) andR^(d32) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3C) substituents;

or, any R^(c32) and R^(d32) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3C)substituents;

each R^(b32) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b32) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3C) substituents;

each R^(3C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a33), SR^(a33),C(O)R^(b33), C(O)NR^(c33)R^(d33), C(O)NR^(c33)(OR^(a33)), C(O)OR^(a33),OC(O)R^(b33), OC(O)NR^(c33)R^(d33), NR^(c33)R^(d33),NR^(c33)C(O)R^(b33), NR^(c33)C(O)OR^(a33), NR^(c33)C(O)NR^(c33)R^(d33),NR^(c33)S(O)R^(b33), NR^(c33)S(O)NR^(c33)R^(d33), NR^(c33)S(O)₂R^(b33),NR^(c33)S(O)₂NR^(c33)R^(d33), S(O)R^(b33), S(O)NR^(c33)R^(d33),S(O)₂R^(b33), S(O)₂NR^(c33)R^(d33), and OS(O)₂R^(b33);

each R^(a33), R^(c33), and R^(d33) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c33) and R^(d33) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b33) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)NR^(c4)R^(d4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), andOS(O)₂R^(b4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

or, any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents;

each R^(b4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(M) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(4A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a41), SR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41), NR^(c41)S(O)R^(b41),NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)₂NR^(c41)R^(d41), S(O)R^(b41), S(O)NR^(c41)R^(d41),S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41), and OS(O)₂R^(b41), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4B) substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b41) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents;

each R^(4B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42),C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42),NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42), NR^(c42)S(O)R^(b42),NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)₂NR^(c42)R^(d42), S(O)R^(b42), S(O)NR^(c42)R^(d42),S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42), and OS(O)₂R^(b42), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(c42) andR^(d42) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4C) substituents;

or, any R^(c42) and R^(d42) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4C)substituents;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b42) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents;

each R^(4C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a43), SR^(a43),C(O)R^(b43), C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43),OC(O)R^(b43), OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43),NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43), NR^(c43)C(O)NR^(c43)R^(d43),NR^(c43)S(O)R^(b43), NR^(c43)S(O)NR^(c43)R^(d43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)₂NR^(c43)R^(d43), S(O)R^(b43), S(O)NR^(c43)R^(d43),S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43), and OS(O)₂R^(b43);

each R^(a43), R^(c43), and R^(d43) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c43) and R^(d43) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group;

each R^(b43) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-;

R⁵ is selected from H, halo, C₂₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5), andOS(O)₂R^(b5), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are each optionally substituted with1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a5), R^(c5) and R^(d5) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

or, any R^(c5) and R^(d5) attached to the same N atom, together with theN atom to which they are attached, form a 5-10 membered heteroaryl or a4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents;

each R^(b5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b5) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(5A) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a51), SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)C(O)R^(b51),NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51),NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51), S(O)NR^(c51)R^(d51),S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51), and OS(O)₂R^(b51), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5B) substituents;

each R^(a51), R^(c51), and R^(d51) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a51), R^(c51) andR^(d51) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5B) substituents;

or, any R^(c51) and R^(d51) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(b51) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b51) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents;

each R^(5B) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a52), SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)C(O)R^(b52),NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52),NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52), S(O)NR^(c52)R^(d52),S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52), and OS(O)₂R^(b52), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5B) areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5C) substituents;

each R^(a52), R^(c52), and R^(d52) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a52), R^(c52) andR^(d52) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5C) substituents;

or, any R^(c52) and R^(d52) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5C)substituents;

each R^(b52) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b52) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5C) substituents;

each R^(5C) is independently selected from halo, oxo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a53), SR^(a53),C(O)R^(b53), C(O)NR^(c53)R^(d53), C(O)NR^(c53)(OR^(a53)), C(O)OR^(a53),OC(O)R^(b53), OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53),NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53), NR^(c53)C(O)NR^(c53)R^(d53),NR^(c53)S(O)R^(b53), NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)₂NR^(c53)R^(d53), S(O)R^(b53), S(O)NR^(c53)R^(d53),S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53), and OS(O)₂R^(b53);

each R^(a53), R^(c53), and R^(d53) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-;

or, any R^(c53) and R^(d53) attached to the same N atom, together withthe N atom to which they are attached, form a 5-6 membered heteroaryl ora 4-7 membered heterocycloalkyl group; and

each R^(b53) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-.

In some embodiments, R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R¹ is selected from H and C₁₋₆ alkyl.

In some embodiments, R¹ is selected from H and methyl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is methyl.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents.

In some embodiment, R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₆cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, and (5-10 membered heteroaryl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, and (5-10 membered heteroaryl)-C₁₋₆ alkyl- of R²are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6membered heteroaryl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6membered heteroaryl)-C₁₋₆ alkyl- of R² are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents.

In some embodiments, R² is selected from H, methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl, wherein the methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl of R² are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents.

In some embodiments, R² is selected from H, methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl, wherein the methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl of R² are each optionally substituted with1 or 2 independently selected R^(2A) substituents.

In some embodiments, each R^(2A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), andS(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents.

In some embodiments, each R^(2A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents.

In some embodiments, each R^(2A) is independently selected from halo,C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents.

In some embodiments, R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents.

In some embodiments, R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents.

In some embodiments, R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1 or 2 independently selectedR^(2B) substituents.

In some embodiments, R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, methyl, ethyl, phenyl, pyridinyl,cyclopropyl, cyclohexyl, dihydroisobenzofuranyl, tetrahydrofuranyl,tetrahydropyranyl, phenylmethyl, cyclohexylmethyl,tetrahydropyranylmethyl, cyclopropylmethyl, and pyridinylmethyl ofR^(a21), R^(b21), R^(c21), and R^(d21) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents.

In some embodiments, R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, methyl, ethyl, phenyl, pyridinyl,cyclopropyl, cyclohexyl, dihydroisobenzofuranyl, tetrahydrofuranyl,tetrahydropyranyl, phenylmethyl, cyclohexylmethyl,tetrahydropyranylmethyl, cyclopropylmethyl, and pyridinylmethyl ofR^(a21), R^(b21), R^(c21), and R^(d21) are each optionally substitutedwith 1 or 2 independently selected R^(2B) substituents.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2C) substituents.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 independently selectedR^(2C) substituents.

In some embodiments, each R^(2C) is independently selected from D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, andOR^(a23).

In some embodiments, each R^(2C) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, andOR^(a23).

In some embodiments, each R^(2C) is independently selected from CN andOR^(a23).

In some embodiments, each R^(a23) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(a23) is H or C₁₋₆ alkyl.

In some embodiments, each R^(a23) is H.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OR^(a23) and CN.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OR^(a23) and CN;

wherein each R^(a23) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OR^(a23) and CN;

wherein each R^(a23) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN; and

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(2B) is independently selected from halo,C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein theC₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN; and

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl.

In some embodiments, each R^(2B) is independently selected from methyl,hydroxy, methoxy, dimethylamino, CN, and C(O)OH.

In some embodiments, R² is selected from H, methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl, wherein the methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl of R² are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents; and eachR^(2A) is independently selected from fluoro, chloro, bromo, methyl,ethyl, piperazinyl, morpholinyl, piperidinyl, morpholinylmethyl,dimethylamino, C(O)OH, C(O)NHCH₃, C(O)NHOCH₃, C(O)NHCH₂CH₂OH,C(O)NHCH₂CH₂OCH₃, C(O)N(CH₃)CH₂CH₂OH, C(O)N(CH₃)CH₂CH₂OCH₃,C(O)NHCH₂C(O)NHNHCH₂-phenyl, C(O)NH-cyclopropyl, C(O)NH-cyclohexyl,C(O)NH-phenyl, C(O)NH-pyridinyl, C(O)N(CH₃)-pyridinyl,C(O)NH-dihydroisobenzofuranyl, C(O)NH-tetrahydrofuranyl,C(O)NH-tetrahydropyranyl, C(O)N(CH₃)-tetrahydropyranyl,C(O)NH-(cyclopropylmethyl), C(O)NH-(cyclohexylmethyl),C(O)NH-(phenylmethyl), C(O)NH-(tetrahydropyranylmethyl),C(O)NH-(pyridinylmethyl), NHC(O)-tetrahydropyranyl, NHC(O)CH₂CN,NHC(O)CH₂CH₃, NHCH₂C(O)OH, NHCH₂CH₂OCH₃, and S(O)₂NH₂, wherein themethyl, ethyl, piperazinyl, morpholinyl, piperidinyl, morpholinylmethyl,C(O)NH-cyclopropyl, C(O)NH-cyclohexyl, C(O)NH-phenyl, C(O)NH-pyridinyl,C(O)N(CH₃)-pyridinyl, C(O)NH-dihydroisobenzofuranyl,C(O)NH-tetrahydrofuranyl, C(O)NH-tetrahydropyranyl,C(O)N(CH₃)-tetrahydropyranyl, C(O)NH-(cyclopropylmethyl),C(O)NH-(cyclohexylmethyl), C(O)NH-(phenylmethyl),C(O)NH-(tetrahydropyranylmethyl), C(O)NH-(pyridinylmethyl), andNHC(O)-tetrahydropyranyl, are each optionally substituted with 1, 2, or3 substituents independently selected from fluoro, methyl, hydroxy,hydroxymethyl, cyano, cyanomethyl, methoxy, and C(O)OH.

In some embodiments, R² is selected from H, methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl, wherein the methyl, ethyl, isopropyl,tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl, pyridinylmethyl,phenylmethyl, and phenylethyl of R² are each optionally substituted with1 or 2 independently selected R^(2A) substituents; and

each R^(2A) is independently selected from fluoro, chloro, bromo,methyl, ethyl, piperazinyl, morpholinyl, piperidinyl, morpholinylmethyl,dimethylamino, C(O)OH, C(O)NHCH₃, C(O)NHOCH₃, C(O)NHCH₂CH₂OH,C(O)NHCH₂CH₂OCH₃, C(O)N(CH₃)CH₂CH₂OH, C(O)N(CH₃)CH₂CH₂OCH₃,C(O)NH-cyclopropyl, C(O)NH— cyclohexyl, C(O)NH-phenyl, C(O)NH-pyridinyl,C(O)N(CH₃)-pyridinyl, C(O)NH-dihydroisobenzofuranyl,C(O)NH-tetrahydrofuranyl, C(O)NH-tetrahydropyranyl,C(O)N(CH₃)-tetrahydropyranyl, C(O)NH-(cyclopropylmethyl),C(O)NH-(cyclohexylmethyl), C(O)NH-(phenylmethyl),C(O)NH-(tetrahydropyranylmethyl), C(O)NH-(pyridinylmethyl),NHC(O)-tetrahydropyranyl, NHC(O)CH₂CN, NHC(O)CH₂CH₃, NHCH₂C(O)OH,NHCH₂CH₂OCH₃, and S(O)₂NH₂, wherein the methyl, ethyl, piperazinyl,morpholinyl, piperidinyl, morpholinylmethyl, C(O)NH— cyclopropyl,C(O)NH-cyclohexyl, C(O)NH-phenyl, C(O)NH-pyridinyl,C(O)N(CH₃)-pyridinyl, C(O)NH-dihydroisobenzofuranyl,C(O)NH-tetrahydrofuranyl, C(O)NH— tetrahydropyranyl,C(O)N(CH₃)-tetrahydropyranyl, C(O)NH-(cyclopropylmethyl),C(O)NH-(cyclohexylmethyl), C(O)NH-(phenylmethyl),C(O)NH-(tetrahydropyranylmethyl), C(O)NH-(pyridinylmethyl), andNHC(O)-tetrahydropyranyl, are each optionally substituted with 1, 2, or3 substituents independently selected from fluoro, methyl, hydroxy,hydroxymethyl, cyano, cyanomethyl, methoxy, and C(O)OH.

In some embodiments, R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R³ is selected from H and C₁₋₆ alkyl.

In some embodiments, R³ is selected from H and methyl.

In some embodiments, R³ is H.

In some embodiments, R³ is C₁₋₆ alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R^(3′) is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R^(3′) is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R^(3′) is selected from H and C₁₋₆ alkyl.

In some embodiments, R^(3′) is H.

In some embodiments, R^(3′) is C₁₋₆ alkyl.

In some embodiments, R³ and R^(3′) are each H.

In some embodiments, R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a4), and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents.

In some embodiments, R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a4), and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents.

In some embodiments, R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), andC(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), andC(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, CN, and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl of R⁴ are each optionally substituted with 1,2, 3, or 4 independently selected R^(4A) substituents.

In some embodiments, R⁴ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, CN, and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl of R⁴ are each optionally substituted with 1or 2 independently selected R^(4A) substituents.

In some embodiments, each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments, each R^(a4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a4) is independently selected from H andC₁₋₆ alkyl.

In some embodiments, each R^(a4), R^(b4), R^(c4), and R^(d4) is anindependently selected C₁₋₆alkyl.

In some embodiments, each R^(a4) is an independently selected C₁₋₆alkyl.

In some embodiments, each R^(a4), R^(b4), R^(c4), and R^(d4) isindependently selected from H and methyl.

In some embodiments, each R^(a4) is independently selected from H andmethyl.

In some embodiments, each R^(a4), R^(b4), R^(c4), and R^(d4) is methyl.

In some embodiments, each R^(a4) is methyl.

In some embodiments, R⁴ is selected from H, methyl, ethenyl,isopropenyl, cyano, iodo, cyclopropyl, cyclohexenyl, phenyl,dihydropyridinyl, pyrazolyl, pyrrolyl, and methoxycarbonyl, wherein themethyl, ethenyl, isopropenyl, cyclopropyl, cyclohexenyl, phenyl,dihydropyridinyl, pyrazolyl, and pyrrolyl of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents.

In some embodiments, R⁴ is selected from H, methyl, ethenyl,isopropenyl, cyano, iodo, cyclopropyl, cyclohexenyl, phenyl,dihydropyridinyl, pyrazolyl, pyrrolyl, and methoxycarbonyl, wherein themethyl, ethenyl, isopropenyl, cyclopropyl, cyclohexenyl, phenyl,dihydropyridinyl, pyrazolyl, and pyrrolyl of R⁴ are each optionallysubstituted with 1 or 2 independently selected R^(4A) substituents.

In some embodiments, each R^(4A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, CN, NO₂, OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), NR^(c41)S(O)R^(b41),NR^(c41)S(O)₂R^(b41), S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41),and S(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl, of R^(4A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents.

In some embodiments, each R^(4A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,NO₂, OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, of R^(4A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents.

In some embodiments, each R^(4A) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,NO₂, OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, of R^(4A) are each optionally substitutedwith 1 or 2 independently selected R^(4B) substituents.

In some embodiments, each R^(4A) is independently selected from halo,C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, CN, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl,5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, of R^(4A)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents.

In some embodiments, each R^(4A) is independently selected from halo,C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, CN, OR^(a41), C(O)R^(b41),C(O)NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl,5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, of R^(4A)are each optionally substituted with 1 or 2 independently selectedR^(4B) substituents.

In some embodiments:

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents; and

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylof R^(b41) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents.

In some embodiments:

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, 4-10 membered heterocycloalkylgroup, wherein the 4-10 membered heterocycloalkyl group is optionallysubstituted with 1 or 2 independently selected R^(4B) substituents; and

each R^(b41) is independently selected from H, C₁₋₆ alkyl, and C₃₋₁₀cycloalkyl.

In some embodiments:

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl-;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, 4-10 membered heterocycloalkylgroup, wherein the 4-10 membered heterocycloalkyl group is optionallysubstituted with 1 or 2 independently selected R^(4B) substituents; and

each R^(b41) is independently selected from C₁₋₆ alkyl and C₃₋₆cycloalkyl.

In some embodiments, each R^(4B) is independently selected from D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a42), SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42),OC(O)R^(b42), OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), and NR^(c42)C(O)OR^(a42), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(4B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents.

In some embodiments, each R^(4B) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a42), SR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42),OC(O)R^(b42), OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42),NR^(c42)C(O)R^(b42), and NR^(c42)C(O)OR^(a42), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(4B) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4C) substituents.

In some embodiments, each R^(4B) is independently selected from C₁₋₆alkyl, CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), NR^(c42)R^(d42),and NR^(c42)C(O)R^(b42), wherein the C₁₋₆ alkyl of R^(4B) is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4C)substituents.

In some embodiments, each R^(4B) is independently selected from C₁₋₆alkyl, CN, OR^(a42), C(O)R^(b42), C(O)NR^(c42)R^(d42), NR^(c42)R^(d42),and NR^(c42)C(O)R^(b42), wherein the C₁₋₆ alkyl of R^(4B) is optionallysubstituted with 1 or 2 independently selected R^(4C) substituents.

In some embodiments:

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and eachR^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments:

each R^(a42), R^(c42), and R^(d42) is independently selected from H andC₁₋₆ alkyl; and each R^(b42) is an independently selected C₁₋₆ alkyl.

In some embodiments, each R^(4C) is independently selected from D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), and C(O)OR^(a43).

In some embodiments, each R^(4C) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), and C(O)OR^(a43).

In some embodiments, each R^(4C) is independently selected fromC(O)R^(b43), C(O)NR^(c43)R^(d43), and C(O)OR^(a43).

In some embodiments, each R^(4C) is C(O)NR^(c43)R^(d43).

In some embodiments, each R^(a43), R^(b43), R^(c43), and R^(d43) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments, each R^(a43), R^(b43), R^(c43), and R^(d43) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a43), R^(b43), R^(c43), and R^(d43) is H.

In some embodiments, each R^(4C) is independently selected from D, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), and C(O)OR^(a43); and

each R^(a43), R^(b43), R^(c43), and R^(d43) is independently selectedfrom H and C₁₋₆ alkyl.

In some embodiments, each R^(4C) is independently selected from halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂,OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), and C(O)OR^(a43); and eachR^(a43), R^(b43), R^(c43), and R^(d43) is independently selected from Hand C₁₋₆ alkyl.

In some embodiments, each R^(4A) is independently selected from chloro,fluoro, methyl, hydroxy, methoxy, cyano, C(O)OH, morpholinyl,piperazinyl, cyclopropyl, phenyl, pyrazolyl, C(O)NH₂, C(O)N(CH₃)_(2J)C(O)NH₂-(cyclopropylmethyl), C(O)NHCH₂CH₃, C(O)NHCH₂CH₂OH, NHC(O)CH₃,SO₂CH₃, SO₂CH₂CH₃, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂-isopropyl, SO₂-cyclopropyl,and SO₂-morpholinyl, wherein the methyl, morpholinyl, piperazinyl,cyclopropyl, phenyl, pyrazolyl, C(O)NH₂-(cyclopropylmethyl),SO₂-isopropyl, SO₂-cyclopropyl, and SO₂-morpholinyl of R^(4A) are eachoptionally substituted with 1 or 2 substituents independently selectedfrom methyl, hydroxy, cyano, dimethylamino, C(O)CH₃, NHC(O)CH₃,C(O)NHCH₃, and CH(CH₃)C(O)NH₂.

In some embodiments, R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5A)substituents.

In some embodiments, R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are eachoptionally substituted with 1 or 2 independently selected R^(5A)substituents.

In some embodiments, R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R⁵ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-,C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R⁵ are each optionally substituted with 1 or 2 independently selectedR^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl of R⁵ are each optionally substituted with 1,2, 3, or 4 independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl,wherein the phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl of R⁵ are each optionally substituted with 1or 2 independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, C₃₋₆ cycloalkyl, andC₆₋₁₀ aryl, wherein the C₃₋₆ cycloalkyl and C₆₋₁₀ aryl are eachoptionally substituted by 1 or 2 independently selected R^(5A)substituents.

In some embodiments, R⁵ is selected from H, halo, C₃₋₆ cycloalkyl, andC₆₋₁₀ aryl, wherein the C₆₋₁₀ aryl is optionally substituted by 1 or 2independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, and C₆₋₁₀ aryl whichis optionally substituted by 1 or 2 independently selected R^(5A)substituents.

In some embodiments, R⁵ is selected from H, halo, C₃₋₆ cycloalkyl, andphenyl wherein the C₃₋₆ cycloalkyl and C₆₋₁₀ aryl are each optionallysubstituted by 1 or 2 independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, C₃₋₆ cycloalkyl, andphenyl wherein the phenyl is optionally substituted by 1 or 2independently selected R^(5A) substituents.

In some embodiments, R⁵ is selected from H, halo, and phenyl which isoptionally substituted by 1 or 2 independently selected R^(5A)substituents.

In some embodiments, each R^(5A) is independently selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(5A) are each optionally substituted with 1, 2, 3, or 4independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is independently selected from C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(5A) are each optionally substituted with 1 or 2independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is independently selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is independently selected from C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionally substitutedwith 1 or 2 independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is independently selected fromphenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-,(5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is independently selected fromphenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-,(5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionally substitutedwith 1 or 2 independently selected R^(5B) substituents.

In some embodiments, each R^(5A) is piperidinylmethyl, which isoptionally substituted by 1 or 2 independently selected R^(5B) groups.

In some embodiments, each R^(5B) is independently selected fromC(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)S(O)R^(b52),NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52).

In some embodiments, each R^(5B) is independently selected fromS(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), andS(O)₂NR^(c52)R^(d52).

In some embodiments, each R^(5B) is independently selected fromS(O)R^(b52) and S(O)₂R^(b52).

In some embodiments, each R^(5B) is S(O)₂R^(b52).

In some embodiments, each R^(a52), R^(b52), R^(c52), and R^(d52) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.

In some embodiments, each R^(a52), R^(b52), R^(c52), and R^(d52) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(a52), R^(b52), R^(c52), and R^(d52) is H.

In some embodiments, each R^(a52), R^(b52), R^(c52), and R^(d52) is anindependently selected C₁₋₆ alkyl.

In some embodiments, each R^(a52), R^(b52), R^(c52), and R^(d52) ismethyl.

In some embodiments, each R^(5B) is S(O)₂R^(b52), wherein each R^(b52)is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R^(5B) is methylsulfonyl.

In some embodiments, R⁵ is selected from H, bromo, cyclopropyl, andphenyl, wherein the phenyl of R⁵ is optionally substituted bypiperidinylmethyl, and wherein the piperidinylmethyl is optionallysubstituted by methyl sulfonyl.

In some embodiments, R⁵ is selected from H, bromo, and phenyl which isoptionally substituted by piperidinylmethyl, wherein thepiperidinylmethyl is optionally substituted by methyl sulfonyl.

In some embodiments:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

R² is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, and (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, and(5-10 membered heteroaryl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

R^(a21), R^(b21), R^(c21), and R^(d21) are each independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(2B) is independently selected from halo, C₁₋₆ alkyl, CN,OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein the C₁₋₆ alkyl isoptionally substituted with 1 or 2 R^(2C) substituents independentlyselected from OH and CN;

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl;

R³ is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

R^(3′) is selected from H, D, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl;

R⁴ is selected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), andC(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl, of R^(4A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylof R^(b41) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents;

each R^(4B) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a42), SR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), andNR^(c42)C(O)OR^(a42), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R^(4B) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(4C) is independently selected from D, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), and C(O)OR^(a43);

each R^(a43), R^(b43), R^(c43), and R^(d43) is independently selectedfrom H and C₁₋₆ alkyl;

R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are each optionally substituted with1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(5A) is independently selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(5B) is independently selected from C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)S(O)R^(b52),NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52); and each R^(a52), R^(b52), R^(c52), andR^(d52) is independently selected from H and C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

R² is selected from H, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, and (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, and(5-10 membered heteroaryl)-C₁₋₆ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

R^(a21), R^(b21), R^(c21), and R^(d21) are each independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(2B) is independently selected from halo, C₁₋₆ alkyl, CN,OR^(a22), C(O)OR^(a22), NR^(c22), R^(d22), wherein the C₁₋₆ alkyl isoptionally substituted with 1 or 2 R^(2C) substituents independentlyselected from OH and CN;

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl;

R³ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

R^(3′) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), andC(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂,OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and4-10 membered heterocycloalkyl, of R^(4A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(a41), R^(c41), and R^(d41) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents;

or, any R^(c41) and R^(d41) attached to the same N atom, together withthe N atom to which they are attached, form a 5-10 membered heteroarylor a 4-10 membered heterocycloalkyl group, wherein the 5-10 memberedheteroaryl or 4-10 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4B)substituents;

each R^(b41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylof R^(b41) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents;

each R^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a42), SR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), andNR^(c42)C(O)OR^(a42), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R^(4B) are each optionally substituted with 1, 2, 3, or 4independently selected R^(4C) substituents;

each R^(a42), R^(c42), and R^(d42) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(4C) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), and C(O)OR^(a43);

each R^(a43), R^(b43), R^(c43), and R^(d43) is independently selectedfrom H and C₁₋₆ alkyl;

R⁵ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁵ are each optionally substituted with1, 2, 3, or 4 independently selected R^(5A) substituents;

each R^(5A) is independently selected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5B)substituents;

each R^(5B) is independently selected from C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)OR^(a52), NR^(c52)S(O)R^(b52),NR^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52),and S(O)₂NR^(c52)R^(d52); and

each R^(a52), R^(b52), R^(c52), and R^(d52) is independently selectedfrom H and C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

R^(a21), R^(b21), R^(c21), and R^(d21) are each independently selectedfrom H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(2B) is independently selected from halo, C₁₋₆ alkyl, CN,OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein the C₁₋₆ alkyl isoptionally substituted with 1 or 2 R^(2C) substituents independentlyselected from OH and CN;

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl;

R³ is selected from H and C₁₋₆ alkyl;

R^(3′) is selected from H and C₁₋₆ alkyl;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(4A) is independently selected from halo, C₁₋₆ alkyl, phenyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,CN, OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, phenyl,C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl, of R^(4A) are each optionally substituted with 1, 2,3, or 4 independently selected R^(4B) substituents;

each R^(4B) is independently selected from C₁₋₆ alkyl, CN, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), NR^(c42)R^(d42), andNR^(c42)C(O)R^(b42), wherein the C₁₋₆ alkyl of R^(4B) is optionallysubstituted with 1 or 2 independently selected R^(4C) substituents;

each R^(a42), R^(b42), R^(c42), and R^(d42) is independently selectedfrom H and C₁₋₆ alkyl;

each R^(4C) is an independently selected C(O)NR^(c43)R^(d43)substituent;

each R^(c43) and R^(d43) is independently selected from H and C₁₋₆alkyl;

R⁵ is selected from H, halo, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl, wherein the phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R⁵ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(5A) substituents;

each R^(5A) is independently selected from phenyl-C₁₋₆ alkyl-, C₃₋₆cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the phenyl-C₁₋₆ alkyl-,C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and(4-6 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1 or 2 independently selected R^(5B)substituents;

each R^(5B) is S(O)₂R^(b52); and

each R^(b52) is independently selected from H and C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

R^(a21), R^(b21), R^(c21), and R^(d21) are each independently selectedfrom H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(2B) is independently selected from halo, C₁₋₆ alkyl, CN,OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), wherein the C₁₋₆ alkyl isoptionally substituted with 1 or 2 R^(2C) substituents independentlyselected from OH and CN;

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl;

R³ is selected from H and C₁₋₆ alkyl; R^(3′) is H;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(4A) is independently selected from chloro, fluoro, methyl,hydroxy, methoxy, cyano, C(O)OH, morpholinyl, piperazinyl, cyclopropyl,phenyl, pyrazolyl, C(O)NH₂, C(O)N(CH₃)_(2J) C(O)NH₂-(cyclopropylmethyl),C(O)NHCH₂CH₃, C(O)NHCH₂CH₂OH, NHC(O)CH₃, SO₂CH₃, SO₂CH₂CH₃, SO₂NHCH₃,SO₂N(CH₃)₂, SO₂-isopropyl, SO₂-cyclopropyl, and SO₂-morpholinyl, whereinthe methyl, morpholinyl, piperazinyl, cyclopropyl, phenyl, pyrazolyl,C(O)NH₂-(cyclopropylmethyl), SO₂-isopropyl, SO₂-cyclopropyl, andSO₂-morpholinyl of R^(4A) are each optionally substituted with 1 or 2substituents independently selected from methyl, hydroxy, cyano,dimethylamino, C(O)CH₃, NHC(O)CH₃, C(O)NHCH₃, and CH(CH₃)C(O)NH₂;

R⁵ is selected from H, halo, C₃₋₆ cycloalkyl, and phenyl, wherein thephenyl is optionally substituted by 1 or 2 independently selected R^(5A)substituents;

each R^(5A) is piperidinylmethyl, which is optionally substituted by 1or 2 independently selected R^(5B) groups;

each R^(5B) is S(O)₂R^(b52); and each R^(b52) is independently selectedfrom H and C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from H and C₁₋₆ alkyl;

R² is selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(2A) is independently selected from halo, C₁₋₆ alkyl, 5-6membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

R^(a21), R^(b21), R^(c21), and R^(d21) are each independently selectedfrom H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(2B) is independently selected from halo, C₁₋₆ alkyl, CN,OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), the C₁₋₆ alkyl is optionallysubstituted with 1 or 2 R^(2C) substituents independently selected fromOH and CN;

each R^(a22), R^(c22), and R^(d22) is independently selected from H andC₁₋₆ alkyl;

R³ is selected from H and C₁₋₆ alkyl;

R^(3′) is H;

R⁴ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents;

each R^(a4) is independently selected from H and C₁₋₆ alkyl;

each R^(4A) is independently selected from chloro, fluoro, methyl,hydroxy, methoxy, cyano, C(O)OH, morpholinyl, piperazinyl, cyclopropyl,phenyl, pyrazolyl, C(O)NH₂, C(O)N(CH₃)_(2J) C(O)NH₂-(cyclopropylmethyl),C(O)NHCH₂CH₃, C(O)NHCH₂CH₂OH, NHC(O)CH₃, SO₂CH₃, SO₂CH₂CH₃, SO₂NHCH₃,SO₂N(CH₃)₂, SO₂-isopropyl, SO₂-cyclopropyl, and SO₂-morpholinyl, whereinthe methyl, morpholinyl, piperazinyl, cyclopropyl, phenyl, pyrazolyl,C(O)NH₂-(cyclopropylmethyl), SO₂-isopropyl, SO₂-cyclopropyl, andSO₂-morpholinyl of R^(4A) are each optionally substituted with 1 or 2substituents independently selected from methyl, hydroxy, cyano,dimethylamino, C(O)CH₃, NHC(O)CH₃, C(O)NHCH₃, and CH(CH₃)C(O)NH₂;

R⁵ is selected from H, halo, and phenyl which is optionally substitutedby 1 or 2 independently selected R^(5A) substituents;

each R^(5A) is piperidinylmethyl, which is optionally substituted by 1or 2 independently selected R^(5B) groups;

each R^(5B) is S(O)₂R^(b52); and

each R^(b52) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, the compound of Formula I is a compound of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,or 4; and variables R¹, R², R³, R⁴, and R^(5A) are defined according tothe definitions provided herein.

In some embodiments, the compound of Formula I is a compound of FormulaIII:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables R¹, R², R³, R⁴, and R^(5B) are defined according tothe definitions provided herein.

In some embodiments, the compound of Formula I is a compound of FormulaIV:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or 4; and variables R¹, R^(2A), R³, R⁴, and R⁵ are defined according tothe definitions provided herein.

In some embodiments, the compound of Formula I is a compound of FormulaV:

or a pharmaceutically acceptable salt thereof, wherein variables R¹,R^(c21), R^(d21), R³, R⁴, and R⁵ are defined according to thedefinitions provided herein.

In some embodiments, the compound of Formula I is a compound of FormulaVI:

or a pharmaceutically acceptable salt thereof, wherein:

n is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4; and

variables R¹, R^(2A), R³, R⁴, and R^(5A) are defined according to thedefinitions provided herein.

In some embodiments, the compound of Formula I is a compound of Formula

or a pharmaceutically acceptable salt thereof, wherein:

m is 0, 1, 2, 3, or 4;

p is 0, 1, 2, 3, or 4; and

variables R¹, R^(2A), R³, R⁴, and R^(5B) are defined according to thedefinitions provided herein.

In some embodiments, the compound provided herein is selected from:

-   4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;-   4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;-   4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-(pyridin-3-ylmethyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;-   2-cyclohexyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;-   4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)cyclohexane-1-carboxylic    acid;-   4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)piperidine-1-sulfonamide;-   2-(4-((2-methoxyethyl)amino)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;-   2-cyano-N-(4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)phenyl)acetamide;-   4-(1,4-dimethyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-(pyridin-3-yl)benzamide;-   4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-methylbenzamide;-   N-(2-(2-benzylhydrazineyl)-2-oxoethyl)-4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzamide;-   4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-((1-cyanocyclopropyl)methyl)benzamide;-   4-(9-(methoxycarbonyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   N-(4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzyl)acetamide;-   4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-methylbenzenesulfonamide;-   9-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:    5,6]pyrido[3,4-d]pyrimidin-3-one;-   2-(4-(4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)phenyl)-1H-pyrazol-1-yl)propanamide;-   4-(9-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(9-(4-(1-aminocyclopropyl)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(4-methyl-9-(1-methyl-1H-pyrrol-3-yl)-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(9-cyclopropyl-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(9-cyano-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;-   and-   4-(8-cyclopropyl-9-(4-methoxyphenyl)-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoic    acid;

or a pharmaceutically acceptable salt thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

Throughout the definitions, the terms “C_(n-m)” and “C_(m-n)” indicatesa range which includes the endpoints, wherein n and m are integers andindicate the number of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, andthe like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 5 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl.

In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In someembodiments, a halo is F. In some embodiments, a halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “cyano-C_(1-n) alkyl” refers to a group offormula —(C_(1-n) alkylene)-CN, wherein the alkyl group has 1 to ncarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms, e.g., —(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C_(1-n) alkyl” refers to a group of formula—(C_(1-n) alkylene)-OH, wherein the alkyl group has 1 to n carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms, e.g., —(C₁₋₃ alkylene)-OH.

As used herein, the term “C_(1-n) alkoxy-C_(1-n) alkyl” refers to agroup of formula —(C_(1-n) alkylene)-O(C_(1-n) alkyl), wherein the alkylgroup has 1 to n carbon atoms. In some embodiments, the alkyl group has1 to 6, 1 to 4, or 1 to 3 carbon atoms, e.g., —(C₁₋₆ alkylene)-O(C₁₋₆alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,or 10 ring-forming carbons (i.e., C₃₋₁₀). In some embodiments, thecycloalkyl is a C₃₋₁₀ monocyclic or bicyclic cycloalkyl. In someembodiments, the cycloalkyl is a C₃₋₇ monocyclic cycloalkyl.

In some embodiments, the cycloalkyl is a C₄₋₇ monocyclic cycloalkyl. Insome embodiments, the cycloalkyl is a C₄₋₁₀ spirocycle or bridgedcycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, S, and B. In some embodiments, the heteroaryl is a5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2heteroatom ring members independently selected from N, O, S, and B. Insome embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1or 2 heteroatom ring members independently selected from N, O, and S. Insome embodiments, the heteroaryl group contains 3 to 10, 4 to 10, 5 to10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments,the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1ring-forming heteroatom.

When the heteroaryl group contains more than one heteroatom ring member,the heteroatoms may be the same or different. Example heteroaryl groupsinclude, but are not limited to, thienyl (or thiophenyl), furyl (orfuranyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl,benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl,triazinyl, thieno[3,2-b]pyridinyl, imidazo[1,2-a]pyridinyl,1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, and thelike.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of a heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). When a ring-forming carbon atom or heteroatom of aheterocycloalkyl group is optionally substituted by one or more oxo orsulfide, the O or S of said group is in addition to the number ofring-forming atoms specified herein (e.g., a1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-memberedheterocycloalkyl group, wherein a ring-forming carbon atom issubstituted with an oxo group, and wherein the 6-memberedheterocycloalkyl group is further substituted with a methyl group).Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having2 fused rings) systems. Included in heterocycloalkyl are monocyclic andpolycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 memberedheterocycloalkyl groups. Heterocycloalkyl groups can also includespirocycles and bridged rings (e.g., a 5 to 10 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring.

In some embodiments, the heterocycloalkyl group contains 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-formingatoms, or 5 to 6 ring-forming atoms. In some embodiments, theheterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkylis a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatomsindependently selected from N, O, S and B and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from N, O, S, and B and having oneor more oxidized ring members. In some embodiments, the heterocycloalkylis a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1,2, 3, or 4 heteroatoms independently selected from N, O, and S andhaving one or more oxidized ring members. In some embodiments, theheterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having1, 2, 3, or 4 heteroatoms independently selected from N, O, and S andhaving one or more oxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one (or2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran,oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline,benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxo-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxo-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl,oxo-2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[1,2-a]pyrazinyl,3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl and the like.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m) alkyl-”, “C_(o-p) aryl-C_(n-m) alkyl-”,“phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m) alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl, or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent (e.g., each R^(M)), areindependently selected at each occurrence from the applicable list.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula I, Formula Ia, etc.) provided herein include stereoisomers ofthe compounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as0-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present disclosure include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present disclosure can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

Compounds of Formula I can be prepared, for example, according to theprocedures described in in Scheme 1. For example,4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine with a suitable protectinggroup (e.g., benzenesulfonyl group) (compound 1-1) can be treated withlithium diisopropyl amide solution and suitable bromination reagent(e.g. dibromotetrachloroethane) to generate compound 1-2. Compound 1-3can be prepared by metal-catalyzed cross coupling reactions (e.g.,Suzuki coupling) of compound 1-2 in the presence of a palladium catalyst(e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and abase (e.g. cesium carbonate or potassium phosphate, tribasic). Compound1-4 can be prepared by metal-catalyzed cross coupling reactions (e.g.,Suzuki coupling) of compound 1-3 with vinylboronic acid in the presenceof a palladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g. cesium carbonate or potassium phosphate, tribasic). Compound 1-5can be prepared by oxidative cleavage conditions (e.g., potassium osmatedihydrate in the presence of sodium periodate). Compound 1-6 can beprepared by reductive amination of compound 1-5 with4-methoxybenzylamine in the presence of acid (e.g., acetic acid) andreducing agent (e.g., sodium cyanoborohydride). Compound 1-6 can beconverted to compound 1-7 using reduction conditions (e.g., iron incombination with ammonium chloride). Compound 1-8 can be prepared byreacting compound 1-7 with coupling reagents (e.g., CDI or triphosgene).Compound 1-9 can be prepared by treating compound 1-8 with suitable base(e.g. sodium hydride) and methylation reagent (e.g., iodomethane).Treating compound 1-9 with strong acid (e.g., TFA) affords compound1-10. Compound 1-11 can be prepared by metal-catalyzed cross couplingreactions (e.g., Buchwald coupling) of compound 1-10 with aryl bromidein the presence of a palladium catalyst (e.g.chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II))and suitable base (e.g. cesium carbonate). Compounds of Formula I (e.g.,compound 1-A of Scheme 1) can be prepared by treating compound 1-11 insuitable deprotection conditions (e.g. when benzene sulfonyl was used asprotecting group, sodium hydroxide was used with water and methanol asco-solvent).

Scheme 1.

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 2. Compound 2-1 can be prepared byreductive amination of compound 1-5 (see Scheme 1) with suitable aminesin the presence of acid (e.g., acetic acid) and reducing agent (e.g.sodium cyanoborohydride). Compound 2-1 can be converted to compound 2-2using reduction conditions (e.g., iron in combination with ammoniumchloride). Compound 2-3 can be prepared by reacting compound 2-2 withcoupling reagents (e.g., CDI or triphosgene). Compound 2-4 can beprepared by treating compound 2-3 with suitable base (e.g. sodiumhydride) and methylation reagent (e.g., iodomethane). The compound ofFormula I (e.g., compound 2-A of Scheme 2) can be prepared by treatingcompound 2-4 in suitable deprotection conditions (e.g. when benzenesulfonyl was used as protecting group, sodium hydroxide was used withwater and methanol as co-solvent).

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 3. Compound 3-1 can be prepared bymetal-catalyzed cross coupling reactions (e.g., Stille coupling) ofcompound 1-3 with tributyl(1-ethoxyvinyl)tin in the presence of apalladium catalyst (e.g., bis(triphenylphosphine)palladium(II)dichloride). The resulting intermediate can be converted to compound 3-1by treating with acid (e.g., in one pot). Compound 3-2 can be preparedby reductive amination of compound 3-1 with suitable amines using acids(e.g. titanium(IV) chloride) and reducing agent (e.g. sodiumcyanoborohydride). Compound 3-2 can be converted to compound 3-3 usingreduction conditions (e.g., iron in combination with ammonium chloride).Compound 3-4 can be prepared by reacting compound 3-3 with couplingreagents (e.g., CDI or triphosgene). Compound 3-5 can be prepared bytreating compound 3-4 with suitable base (e.g. sodium hydride) andmethylation reagent (e.g., iodomethane). The compound of Formula I(e.g., compound 3-A of Scheme 3) can be prepared by treating compound3-5 in suitable deprotection conditions (e.g. when benzene sulfonyl wasused as protecting group, sodium hydroxide was used with water andmethanol as co-solvent).

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 4. Compound 4-1 can be prepared byreductive amination of compound 1-5 (see Scheme 1) with t-butylamine inthe presence of acid (e.g., acetic acid) and reducing agent (e.g. sodiumcyanoborohydride). Compound 4-1 can be converted to compound 4-2 usingreduction conditions (e.g., iron in combination with ammonium chloride).Compound 4-3 can be prepared by reacting compound 4-2 with couplingreagents (e.g., CDI or triphosgene). Compound 4-4 can be prepared bytreating compound 4-3 with suitable base (e.g. sodium hydride) andmethylation reagent (e.g., iodomethane). Treating compound 4-4 withstrong acid (e.g., TFA) would afford desired compound 4-5. Compound 4-6can be prepared by metal-catalyzed cross coupling reactions (e.g.,Buchwald coupling) of compound 4-5 with aryl bromide in the presence ofa palladium catalyst (e.g.chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II))and suitable base (e.g. cesium carbonate). The compound of Formula I(e.g., compound 4-A of Scheme 4) can be prepared by treating compound4-6 in suitable deprotection conditions (e.g. when benzene sulfonyl wasused as protecting group, sodium hydroxide was used with water andmethanol as co-solvent).

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 5. For example,4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine with a suitable protectinggroup (e.g., benzenesulfonyl group) (see compound 1-1, Scheme 1) can beused as starting material. Compound 5-1 can be prepared bymetal-catalyzed cross coupling reactions (e.g., Suzuki coupling) ofcompound 1-1 with vinylboronic acid in the presence of a palladiumcatalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g. cesium carbonate or potassium phosphate, tribasic). Compound 5-2can be prepared by oxidative cleavage conditions (e.g., potassium osmatedihydrate in the presence of sodium periodate). Compound 5-3 can beprepared by reductive amination of compound 5-2 with suitable amines inthe presence of acid (e.g., acetic acid) and reducing agent (e.g. sodiumcyanoborohydride). Compound 5-3 can be converted to compound 5-4 usingreduction conditions (e.g., iron in combination with ammonium chloride).Compound 5-5 can be prepared by reacting compound 5-4 with couplingreagents (e.g., CDI or triphosgene).

Compound 5-6 can be prepared by treating compound 5-5 with suitable base(e.g. sodium hydride) and methylation reagent (e.g., iodomethane).Compound 5-6 can be treated with lithium diisopropyl amide solution andsuitable bromination reagent (e.g. dibromotetrachloroethane) to generatedesired compound 5-7. Compound 5-8 can be prepared by metal-catalyzedcross coupling reactions (e.g., Suzuki coupling) of compound 5-7 in thepresence of a palladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g. cesium carbonate or potassium phosphate, tribasic). Treatingcompound 5-8 with strong acid (e.g., TFA) would afford the desiredcompound 5-9. Compound 5-10 can be prepared by metal-catalyzed crosscoupling reactions (e.g., Buchwald coupling) of compound 5-9 with arylbromide in the presence of a palladium catalyst (e.g.,chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II))and suitable base (e.g. cesium carbonate). The compound of Formula I(e.g., compound 5-A of Scheme 5) can be prepared by treating compound5-10 in suitable deprotection conditions (e.g. when benzene sulfonyl wasused as protecting group, sodium hydroxide was used with water andmethanol as co-solvent).

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 6. Compounds 1-9 (see Scheme 1) or5-8 (see Scheme 5) can be deprotected under suitable conditions (e.g.when benzene sulfonyl was used as protecting group, sodium hydroxide wasused with water and methanol as co-solvent) to afford compound 6-1.Compound 6-1 can be halogenated with a halogenating reagent (e.g., NBSor NIS), to afford compound 6-2. Compound 6-2 can be protected (e.g.,with (Boc)₂O), to afford compound 6-3. Compound 6-4 can be prepared bymetal-catalyzed cross coupling reactions (e.g., Suzuki coupling) ofcompound 6-3 in the presence of a palladium catalyst (e.g.,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g., cesium carbonate or potassium phosphate, tribasic).Alternatively, compound 6-4 can be prepared by other metal-catalyzedcross coupling reactions (e.g., Negishi coupling) of compound 6-3 in thepresence of a palladium catalyst (e.g.tetrakis(triphenylphospine)palladium(O)). Compound 6-4 can also beprepared through a sulfonylation of compound 6-3 with a sodiumalkylsulfinate in the presence of Cu(I) (e.g. copper(I) iodide) or acarbonylation of compound 6-3 with carbon monoxide in the presence of apalladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and atertiary amine base. The compound of Formula I (e.g., compound 6-A ofScheme 6) can be prepared by treating compound 6-4 with suitabledeprotection conditions such as TFA in dichloromethane.

Compounds of Formula I can also be prepared, for example, according tothe procedures described in Scheme 7. Compound 5-2 (see Scheme 5) can beconverted to compound 7-1 by reductive amination of compound 5-2 withtert-butyl 4-aminobenzoate in the presence of acid (e.g. acetic acid)and a reducing agent (e.g. sodium cyanoborohydride). Compound 7-1 can beconverted to compound 7-2 using reduction conditions (e.g., iron incombination with ammonium chloride). Compound 7-3 can be prepared byreacting compound 7-2 with coupling reagents (e.g., CDI or triphosgene).

Compound 7-4 can be prepared by treating compound 7-3 with suitable base(e.g. cesium carbonate) and methylation reagent (e.g., iodomethane).Compound 7-4 can be treated with lithium diisopropyl amide solution andsuitable bromination reagent (e.g. dibromotetrachloroethane) to generatedesired compound 7-5. Compound 7-6 can be prepared by metal-catalyzedcross coupling reactions (e.g., Suzuki coupling) of compound 7-5 in thepresence of a palladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g. cesium carbonate or potassium phosphate, tribasic). Compound 7-7can be prepared by treating compound 7-6 in suitable deprotectionconditions (e.g. when benzene sulfonyl was used as protecting group,sodium hydroxide was used with water and methanol as co-solvent).

Compound 7-7 can be halogenated with a halogenating reagent (e.g., NBSor NIS), to afford compound 7-8. Compound 7-8 can be protected (e.g.,with (Boc)₂O), to give compound 7-9. Compound 7-10 can be prepared bymetal-catalyzed cross coupling reactions (such as Suzuki coupling) ofcompound 7-9 in the presence of a palladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base(e.g. cesium carbonate or potassium phosphate, tribasic). Alternatively,compound 7-10 can be prepared by other metal-catalyzed cross couplingreactions (e.g., Negishi coupling) of compound 7-9 in the presence of apalladium catalyst (e.g. tetrakis(triphenylphospine)palladium(0)).Compound 7-10 can also be prepared through a sulfonylation of compound7-9 with a sodium alkylsulfinate in the presence of Cu(I) (e.g.copper(I) iodide) or a carbonylation of compound 7-9 with carbonmonoxide in the presence of a palladium catalyst (e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and atertiary amine base.

Compound 7-11 can be prepared by treating compound 7-10 with suitabledeprotection conditions (e.g., TFA in dichloromethane). Carboxylic acid7-11 can be coupled with an appropriately substituted amine understandard amide formation conditions (e.g., in the presence of a couplingreagent, such as HATU, and amine, such as diisopropylethylamine) or byconversion of acid 7-11 to the acid chloride (e.g., with oxalylchloride) and condensing with an appropriately substituted amine) toafford the compound of Formula I (e.g., compound 7-A of Scheme 7).

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature”, or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart.

For example, product formation can be monitored by spectroscopic means,such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C),infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC).

Compounds can be purified by those skilled in the art by a variety ofmethods, including high performance liquid chromatography (HPLC) andnormal phase silica chromatography.

Methods of Use

The compounds described herein can inhibit the activity of the V617Fvariant of the protein-tyrosine kinase JAK2 (i.e., “V617F” or“JAK2V617F”). Compounds which inhibit V617F are useful in providing ameans of preventing the growth or inducing apoptosis in tumors,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds of the disclosure are useful in treating orpreventing proliferative disorders such as cancers. In particular tumorswith activating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors.

In certain embodiments, the disclosure provides a method for treating aV617F-related disorder in a patient in need thereof, comprising the stepof administering to said patient a compound of the disclosure, or apharmaceutically acceptable composition thereof.

Myeloproliferative diseases (MPD) are multipotent hematopoietic stemcell disorders characterized by excess production of various bloodcells. MPNs include polycythemia vera (PV), essential thrombocythemia(ET), and idiopathic myelofibrosis (IMF). JAK2 V617F mutation isreported in about 95% of patients with PV, in 35% to 70% of patientswith ET, and 50% of patients with IMF. Also, JAK2 exon 12 mutations aredetected in some of the V617F-negative PV patients (Ma et al., J. Mol.Diagn., 11: 49-53, 2009). In some embodiments, the compounds of thedisclosure can be useful in the treatment of myeloproliferativedisorders (e.g., myeloproliferative neoplasms) in a patient in needthereof, such as polycythemia vera, essential thrombocythemia,myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis(PMF), chronic myelogenous leukemia (CML), chronic myelomonocyticleukemia (CMML), hypereosinophilic syndrome (HES), systemic mast celldisease (SMCD), and the like.

In some embodiments, the myeloproliferative disorder is amyeloproliferative neoplasm.

In some embodiments, the myeloproliferative disorder is myelofibrosis(e.g., primary myelofibrosis (PMF) or post polycythemia vera/essentialthrombocythemia myelofibrosis (Post-PV/ET MF)).

In some embodiments, the myeloproliferative disorder is primarymyelofibrosis (PMF).

In some embodiments, the myeloproliferative disorder is post- essentialthrombocythemia myelofibrosis (Post-ET MF).

In some embodiments, the myeloproliferative disorder is postpolycythemia vera myelofibrosis (Post-PV MF).

In some embodiments, the myeloproliferative disorder is selected fromprimary myelofibrosis (PMF), polycythemia vera (PV), and essentialthrombocythemia (ET).

In some embodiments, the myeloproliferative neoplasm is primarymyelofibrosis (PMF).

In some embodiments, the myeloproliferative neoplasm is polycythemiavera (PV).

In some embodiments, the myeloproliferative neoplasm is essentialthrombocythemia (ET).

Myeloproliferative diseases include disorders of a bone marrow or lymphnode-derived cell type, such as a white blood cell. A myeloproliferativedisease can manifest by abnormal cell division resulting in an abnormallevel of a particular hematological cell population. The abnormal celldivision underlying a proliferative hematological disorder is typicallyinherent in the cells and not a normal physiological response toinfection or inflammation. Leukemia is a type of myeloproliferativedisease. Exemplary myeloproliferative diseases include, but are notlimited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia(ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome(MDS), chronic myeloid leukemia (CML), hairy cell leukemia, leukemicmanifestations of lymphomas, multiple myeloma, polycythemia vera (PV),essential thrombocythemia (ET), idiopathic myelofibrosis (IMF),hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL),myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocyticleukemia (CMML), juvenile myelomonocytic leukemia, chronic basophilicleukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), andunclassified myeloproliferative diseases (UMPD or MPD-NC). Lymphoma is atype of proliferative disease that mainly involves lymphoid organs, suchas lymph nodes, liver, and spleen. Exemplary proliferative lymphoiddisorders include lymphocytic lymphoma (also called chronic lymphocyticleukemia), follicular lymphoma, large cell lymphoma, Burkitt's lymphoma,marginal zone lymphoma, lymphoblastic lymphoma (also called acutelymphoblastic lymphoma).

For example, the compounds of the disclosure are useful in the treatmentof cancer. Example cancers include bladder cancer (e.g., urothelialcarcinoma, squamous cell carcinoma, adenocarcinoma), breast cancer(e.g., hormone R positive, triple negative), cervical cancer, colorectalcancer, cancer of the small intestine, colon cancer, rectal cancer,cancer of the anus, endometrial cancer, gastric cancer (e.g.,gastrointestinal stromal tumors), head and neck cancer (e.g., cancers ofthe larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth,squamous head and neck cancers), kidney cancer (e.g., renal cellcarcinoma, urothelial carcinoma, sarcoma, Wilms tumor), liver cancer(e.g., hepatocellular carcinoma, cholangiocellular carcinoma (e.g.,intrahepatic, hilar or perihilar, distal extrahepatic), liverangiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, smallcell lung cancer and non-small cell lung carcinomas, parvicellular andnon-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma,pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicularcancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladdercancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomachcancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g.,pheochromocytoma, Merkel cell cancer, neuroendocrine carcinoma), skincancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skincancer), and brain cancer (e.g., astrocytoma, medulloblastoma,ependymoma, neuro-ectodermal tumors, pineal tumors).

Further example cancers include hematopoietic malignancies such asleukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma,adult T cell leukemia, acute myeloid leukemia (AML), B-cell lymphoma,cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin's ornon-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., 8p11myeloproliferative syndrome, polycythemia vera (PV), essentialthrombocythemia (ET), and primary myelofibrosis (PMF)), myelodysplasticsyndrome, chronic eosinophilic leukemia, Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma,acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt'slymphoma.

In certain embodiments, provided herein is a method of treating cancercomprising administering to a patient in need thereof a therapeuticallyeffect amount of a compound of the disclosure. In certain embodiments,the cancer is selected from T lymphoblastic lymphoma, glioblastoma,melanoma, rhabdosarcoma, lymphosarcoma, and osteosarcoma.

Other cancers treatable with the compounds of the disclosure includetumors of the eye, glioblastoma, melanoma, leiomyosarcoma, andurothelial carcinoma (e.g., ureter, urethra, bladder, urachus).

The compounds of the disclosure can also be useful in the inhibition oftumor metastases.

In some embodiments, the compounds of the disclosure as described hereincan be used to treat Alzheimer's disease, HIV, or tuberculosis.

In some embodiments, the compounds of the disclosure can be useful inthe treatment of myelodysplastic syndrome (MDS) in a patient in needthereof. In some embodiments, said patient having the myelodysplasticsyndrome (MDS) is red blood cell transfusion dependent.

As used herein, myelodysplastic syndromes are intended to encompassheterogeneous and clonal hematopoietic disorders that are characterizedby ineffective hematopoiesis on one or more of the major myeloid celllineages. Myelodysplastic syndromes are associated with bone marrowfailure, peripheral blood cytopenias, and a propensity to progress toacute myeloid leukemia (AML). Moreover, clonal cytogenetic abnormalitiescan be detected in about 50% of cases with MDS. In 1997, The WorldHealth Organization (WHO) in conjunction with the Society forHematopathology (SH) and the European Association of Hematopathology(EAHP) proposed new classifications for hematopoietic neoplasms (Harris,et al., J Clin Oncol 1999; 17:3835-3849; Vardiman, et al., Blood 2002;100:2292-2302). For MDS, the WHO utilized not only the morphologiccriteria from the French-American-British (FAB) classification but alsoincorporated available genetic, biologic, and clinical characteristicsto define subsets of MDS (Bennett, et al., Br. J. Haematol. 1982;51:189-199). In 2008, the WHO classification of MDS (Table 1) wasfurther refined to allow precise and prognostically relevantsubclassification of unilineage dysplasia by incorporating new clinicaland scientific information (Vardiman, et al., Blood 2009; 114:937-951;Swerdlow, et al., WHO Classification of Tumours of Haematopoietic andLymphoid Tissues. 4th Edition. Lyon France: IARC Press; 2008:88-103;Bunning and Germing, “Myelodysplastic syndromes/neoplasms” in Chapter 5,Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoieticand Lymphoid Tissues. (ed. 4th edition): Lyon, France: IARC Press;2008:88-103).

TABLE 1 2008 WHO Classification for De Novo Myelodysplastic SyndromeSubtype Blood Bone Marrow Refractory cytopenia with Single orBicytopenia Dysplasia in ≥10% of 1 cell unilineage dysplasia line, <5%blasts (RCUD) Refractory anemia with Anemia, no blasts ≥15% of erythroidprecursors ring sideroblasts (RARS) w/ring sideroblasts, erythroiddysplasia only, <5% blasts Refractory cytopenia with Cytopenia(s), <1 ×10⁹/L Dysplasia in ≥10% of cells in ≥2 multilineage dysplasia monocyteshematopoietic lineages, ±15% ring sideroblasts, <5% blasts Refractoryanemia with Cytopenia(s), ≤2% to 4% Unilineage or multilineage excessblasts-1 (RAEB-1) blasts, <1 × 10⁹/L dysplasia, No Auer rods, 5% tomonocytes 9% blasts Refractory anemia with Cytopenia(s), ≤5% to 19%Unilineage or multilineage excess blasts-2 (RAEB-2) blasts, <1 × 10⁹/Ldysplasia, ±Auer rods, 10% to monocytes 19% blasts MyelodysplasticCytopenias Unilineage or no dysplasia but syndrome, unclassifiedcharacteristic MDS (MDS-U) cytogenetics, <5% blasts MDS associated withAnemia, platelets Unilineage erythroid. Isolated isolated del(5q) normalor increased del(5q), <5% blasts

In some embodiments, the myelodysplastic syndrome is refractorycytopenia with unilineage dysplasia (RCUD).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith ring sideroblasts (RARS).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith ring sideroblasts associated with thrombocytosis (RARS-T).

In some embodiments, the myelodysplastic syndrome is refractorycytopenia with multilineage dysplasia.

In some embodiments, the myelodysplastic syndrome is refractory anemiawith excess blasts-1 (RAEB-1).

In some embodiments, the myelodysplastic syndrome is refractory anemiawith excess blasts-2 (RAEB-2).

In some embodiments, the myelodysplastic syndrome is myelodysplasticsyndrome, unclassified (MDS-U).

In some embodiments, the myelodysplastic syndrome is myelodysplasticsyndrome associated with isolated del(5q).

In some embodiments, the myelodysplastic syndrome is refractory toerythropoiesis-stimulating agents.

In some embodiments, the compounds of the disclosure can be useful inthe treatment of myeloproliferative disorder/myelodysplastic overlapsyndrome (MPD/MDS overlap syndrome).

In some embodiments, the compounds of the disclosure can be useful inthe treatment of leukemia.

In some embodiments, the compounds of the disclosure can be useful inthe treatment of acute myeloid leukemia (AML).

In addition to oncogenic neoplasms, the compounds of the disclosure canbe useful in the treatment of skeletal and chondrocyte disordersincluding, but not limited to, achrondroplasia, hypochondroplasia,dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II),Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome,Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, andcraniosynostosis syndromes.

The compounds provided herein may further be useful in the treatment offibrotic diseases, such as where a disease symptom or disorder ischaracterized by fibrosis.

Example fibrotic diseases include liver cirrhosis, glomerulonephritis,pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and woundhealing.

In some embodiments, the compounds provided herein can be used in thetreatment of a hypophosphatemia disorder such as, for example, X-linkedhypophosphatemic rickets, autosomal recessive hypophosphatemic rickets,and autosomal dominant hypophosphatemic rickets, or tumor-inducedosteromalacia.

In some embodiments, provided herein is a method of increasing survivalor progression-free survival in a patient, comprising administering acompound provided herein to the patient. In some embodiments, thepatient has cancer. In some embodiments, the patient has a disease ordisorder described herein. As used herein, progression-free survivalrefers to the length of time during and after the treatment of a solidtumor that a patient lives with the disease but it does not get worse.Progression-free survival can refer to the length of time from firstadministering the compound until the earlier of death or progression ofthe disease. Progression of the disease can be defined by RECIST v. 1.1(Response Evaluation Criteria in Solid Tumors), as assessed by anindependent centralized radiological review committee. In someembodiments, administering of the compound results in a progression freesurvival that is greater than about 1 month, about 2 months, about 3months, about 4 months, about 5 months, about 6 months, about 8 months,about 9 months, about 12 months, about 16 months, or about 24 months. Insome embodiments, the administering of the compound results in aprogression free survival that is at least about 1 month, about 2months, about 3 months, about 4 months, about 5 months, about 6 months,about 8 months, about 9 months, or about 12 months; and less than about24 months, about 16 months, about 12 months, about 9 months, about 8months, about 6 months, about 5 months, about 4 months, about 3 months,or about 2 months. In some embodiments, the administering of thecompound results in an increase of progression free survival that is atleast about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 8 months, about 9 months, or about12 months; and less than about 24 months, about 16 months, about 12months, about 9 months, about 8 months, about 6 months, about 5 months,about 4 months, about 3 months, or about 2 months.

The present disclosure further provides a compound described herein, ora pharmaceutically acceptable salt thereof, for use in any of themethods described herein.

The present disclosure further provides use of a compound describedherein, or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in any of the methods describedherein.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a V617F variant with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having a V617F variant, as wellas, for example, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the V617Fvariant.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21 st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the disclosure which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapies

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment or prevention ofV617F-associated diseases, disorders or conditions, or diseases orconditions as described herein. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD19, CD47, CDK2, STING,ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 forthe treatment of diseases and disorders. Exemplary diseases anddisorders include cancer, infection, inflammation and neurodegenerativedisorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with targeted therapies,including JAK kinase inhibitors (ruxolitinib, additional JAK1/2 andJAK1-selective, baricitinib or itacitinib), Pim kinase inhibitors (e.g.,LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors includingPI3K-delta selective and broad spectrum PI3K inhibitors (e.g., INCB50465and INCB50797), PI3K-gamma inhibitors such as PI3K-gamma selectiveinhibitors, MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 andLY3022855), TAM receptor tyrosine kinases inhibitors (Tyro-3, Axl, andMer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptorinhibitors, Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (Bortezomib, Carfilzomib),HDAC-inhibitors (panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family membersinhibitors (for example, bromodomain inhibitors or BET inhibitors, suchas OTX015, CPI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g.,GSK2979552, INCB59872 and INCB60003), arginase inhibitors (e.g.,INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat,NLG919 or BMS-986205), PARP inhibiors (e.g., olaparib or rucaparib), andinhibitors of BTK such as ibrutinib.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671, US20170174679, US 20170320875, US 20170342060, US 20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is retifanimab (alsoknown as MGA012), nivolumab, pembrolizumab (also known as MK-3475),pidilizumab, SHR-1210, PDR001, ipilumimab or AMP-224. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab.In some embodiments, the anti-PD-1 monoclonal antibody is retifanimab(also known as MGA012). In some embodiments, the anti-PD1 antibody isSHR-1210. Other anti-cancer agent(s) include antibody therapeutics suchas 4-1BB (e.g. urelumab, utomilumab).

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with FGFR inhibitors. These includeonartumzumab, tivantnib, and capmatinib (also known as INC-280). Agentsagainst Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, andponatinib and those against Alk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith inhibitors described herein. These include antibodies against VEGFor VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeuticproteins against VEGF include bevacizumab and aflibercept. Inhibitors ofVEGFR kinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with compounds describedherein. Other suitable examples include but are not limited tovemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetiniband GDC-0973 (MEK inhibitors). Inhibitors of one or more JAKs (e.g.,ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin),cyclin dependent kinases (e.g., palbociclib), HDACs (e.g.,panobinostat), PARP (e.g., olaparib), and proteasomes (e.g., bortezomib,carfilzomib) can also be combined with compounds described herein. Insome embodiments, the JAK inhibitor is selective for JAK1 over JAK2 andJAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (e.g., vincaalkaloids, antitumor antibiotics, enzymes, lymphokines andepipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin (see e.g., U.S. Pat. Nos. 9,233,985, 10,065,974,10,287,303, 8,524,867, the disclosures of which are incorporated byreference herein in their entireties).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating V617F in tissue samples,including human, and for identifying V617F inhibitors by binding of alabeled compound. Substitution of one or more of the atoms of thecompounds of the present disclosure can also be useful in generatingdifferentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes V617F assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, >5S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula I can be optionally substituted with deuterium atoms, such as—CD₃ being substituted for —CH₃). In some embodiments, alkyl groups ofthe disclosed Formulas (e.g., Formula I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, 1-6, 1-8, 1-10,1-12, 1-14, 1-16, 1-18, or 1-20 deuterium atoms. In some embodiments,all of the hydrogen atoms in a compound can be replaced or substitutedby deuterium atoms.

In some embodiments, each hydrogen atom of the compounds providedherein, such as hydrogen atoms attached to carbon atoms of alkyl,alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, orheteroaryl substituents or —C₁₋₄ alkyl-, alkylene, alkenylene, andalkynylene linking groups, as described herein, is optionally replacedby deuterium atoms.

In some embodiments, each hydrogen atom of the compounds providedherein, such as hydrogen atoms to carbon atoms of alkyl, alkenyl,alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroarylsubstituents or —C₁₋₄ alkyl-, alkylene, alkenylene, and alkynylenelinking groups, as described herein, is replaced by deuterium atoms(i.e., the alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents, or —C₁₋₄ alkyl-, alkylene,alkenylene, and alkynylene linking groups are perdeuterated).

In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogenatoms, attached to carbon atoms of alkyl, alkenyl, alkynyl, aryl,phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents or—C₁₋₄ alkyl-, alkylene, alkenylene, and alkynylene linking groups, asdescribed herein, are optionally replaced by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises at least one deuterium atom.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises two or more deuterium atoms.

In some embodiments, the compound provided herein (e.g., the compound ofany of Formulas I-VII), or a pharmaceutically acceptable salt thereof,comprises three or more deuterium atoms.

In some embodiments, for a compound provided herein (e.g., the compoundof any of Formulas I-VII), or a pharmaceutically acceptable saltthereof, all of the hydrogen atoms are replaced by deuterium atoms(i.e., the compound is “perdeuterated”).

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro V617F labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ²⁵I, ¹³¹I or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind V617F by monitoring its concentrationvariation when contacting with V617F, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to V617F(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to V617F directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of V617F-associated diseases ordisorders as described herein, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the disclosure. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 30×100 mm or WatersXBridge™ C₁₈ 5 μm, 30×100 mm column, eluting with mobile phase A: 0.1%TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile;the flow rate was 60 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature (see e.g. “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Example 1.4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

Step 1.4-(Methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine

To a solution of2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3000mg, 10.10 mmol) in dimethylformamide (40 ml) was added cesium carbonate(9873 mg, 30.3 mmol) and 4-(methylsulfonyl)piperidine (1814 mg, 11.11mmol). The resulting solution was stirred at room temperature (r.t.) for1 hour. After this time, the reaction mixture was diluted with ethylacetate and then washed with water and brine. The organic layer wasdried over MgSO₄, filtered, and then concentrated to dryness. Theresulting residue was used for next step without purification. LC-MScalculated for C₁₉H₃₁BNO₄S (M+H)⁺: m/z=380.2; found 380.2.

Step 2.2-Bromo-4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (AurumPharmatech, catalog number Q-3100, 20 g, 59.2 mmol) in tetrahydrofuran(250 ml) was added lithium diisopropylamide solution (2.OM intetrahydrofuran/heptane/ethylbenzene, 89 mL, 178 mmol) over 10 minutesat −78° C. The resulting solution was stirred at −78° C. for 30 minutes,then 1,2-dibromo-1,1,2,2-tetrachloroethane (38.6 g, 118 mmol) intetrahydrofuran was added and the resulting solution was then warmed upto r.t. over 30 minutes and stirred at r.t. for 1 hour. After this time,the reaction was quenched by addition of 1N HCl and then extracted byethyl acetate. The organic layer was then washed with water and brine,dried over MgSO₄, filtered, and then concentrated to dryness. Theresidue was purified by silica gel chromatography using 0-100% ethylacetate in hexanes to afford the desired product (14.2 g, 34.1 mmol) asa brownish solid. LC-MS calculated for C₁₃H₈BrClN₃O₄S (M+H)⁺: m/z=415.9;found 415.9.

Step 3.2-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine

To a solution of2-bromo-4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(699 mg, 1.677 mmol) and4-(methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine(530 mg, 1.397 mmol) in dioxane (10 mL) and water (2.5 mL) was addedcesium carbonate (1821 mg, 5.59 mmol) and1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (228 mg,0.279 mmol).

Nitrogen was bubbled through the solution for 5 minutes then thesolution was stirred at 70° C. for 2 hours. After this time,4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (323 mg, 2.096 mmol) wasadded and the mixture was stirred for 3 hours at 100° C. The resultingsolution was then cooled to r.t., water was removed, the organic layerwas concentrated to dryness, and the resulting residue was purified bysilica gel chromatography using 0-100% ethyl acetate in hexanes toafford desired product as yellowish oil (640 mg, 79%). LC-MS calculatedfor C₂₈H₂₉N₄O₆S₂ (M+H)⁺: m/z=581.2; found 581.2.

Step 4.2-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine(400 mg, 0.689 mmol) in THE (4 mL) and water (4.00 mL) was added sodiumperiodate (442 mg, 2.067 mmol) and potassium osmate dihydrate (12.69 mg,0.034 mmol). The resulting solution was stirred at r.t. for 2 hours thendiluted with dichloromethane (DCM) and then washed with water and brine.The organic layer was dried over MgSO₄, filtered, and then concentratedto dryness. The resulting residue was purified by silica gelchromatography using 0-20% methanol in DCM to afford desired product asyellowish oil (156 mg, 38.9%). LC-MS calculated for C₂₇H₂₇N₄O₇S₂ (M+H)⁺:m/z=583.1; found 583.1.

Step 5.4-(((2,4-Dimethoxybenzyl)amino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(1700 mg, 2.92 mmol) in dichloromethane (20 mL) was added(2,4-dimethoxyphenyl)methanamine (1464 mg, 8.75 mmol) and acetic acid(835 μL, 14.59 mmol), and the resulting mixture was stirred at r.t. for1 hour. Next, sodium cyanoborohydride (550 mg, 8.75 mmol) was added inone portion. The solution was then stirred at r.t. for 1 hour, thendiluted with dichloromethane and washed with sodium bicarbonate solutionand brine. The organic layer was dried over MgSO₄, filtered, and thenconcentrated to dryness. The residue was then dissolved in THE (10.0mL), MeOH (10.0 mL), and water (10.0 mL). To the resulting suspensionwas added iron (815 mg, 14.59 mmol) and ammonium chloride (780 mg, 14.59mmol) and the mixture was stirred at 80° C. for 15 hours. After thistime, the mixture was cooled to r.t., diluted with 1:1 methanol anddichloromethane, and then filtered. The filtrate was concentrated todryness the resulting residue was purified by silica gel chromatographyusing 0-60% methanol in DCM to afford desired product as brownish oil.LC-MS calculated for C₃₆H₄₂N₅O₆S₂(M+H)⁺: m/z=704.3; found 704.3.

Step 6.2-(2,4-Dimethoxybenzyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of4-(((2,4-dimethoxybenzyl)amino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine(1400 mg, 1.989 mmol) in THF (40 mL) and DMF (5.0 mL) at 0° C. was addedtriethylamine (1386 μL, 9.94 mmol) and triphosgene (472 mg, 1.591 mmol,pre-dissolved in 5 mL THF). The reaction mixture was stirred at 0° C.for 10 minutes then warmed to r.t. After this time, the reaction mixturewas quenched by aqueous sodium hydroxide solution then extracted withethyl acetate. The organic layer was washed with brine then dried overMgSO₄, filtered, and then concentrated to dryness. The resulting residuewas dissolved in DMF (20.0 mL) then iodomethane (187 μL, 2.98 mmol) andsodium hydride (119 mg, 2.98 mmol) were added. The resulting solutionwas stirred at r.t. for 30 minutes then quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, filtered, and then concentrated to dryness. Theresidue was purified by silica gel chromatography using 0-30% methanolin DCM to afford desired product as brownish oil (500 mg, 33.8%). LC-MScalculated for C₃₈H₄₂N₅O₇S₂(M+H)⁺: m/z=744.2; found 744.4.

Step 7.4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

2-(2,4-dimethoxybenzyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one(500 mg, 0.672 mmol) was dissolved in trifluoroacetic acid (TFA, 5 mL,64.9 mmol) and then stirred at r.t. for 1 hour. After this time, thereaction mixture was diluted with DCM and then washed with 1N NaOHsolution. The organic layer was dried over MgSO₄, filtered, and thenconcentrated to dryness. The resulting residue was purified by silicagel chromatography using 0-40% methanol in DCM to afford desired productas brownish oil (350 mg, 48.7%). LC-MS calculated for C₂₉H₃₂N₅O₅S₂(M+H)⁺: m/z=594.2; found 594.1.

Step 8.4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one(20 mg, 0.034 mmol) in 1 mL methanol was added 1 mL 2.5 M NaOH solution.The resulting solution was stirred at 80° C. for 1 hour and then cooledto r.t. The reaction mixture was then diluted with acetonitrile,filtered, and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% NH₄OH, at flow rate of 60mL/min) to afford the desired compound. LC-MS calculated for C₂₃H₂₈N₅O₃S(M+H)⁺: m/z=454.2; found 454.4.

Example 2.4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrimidin-3-one

Step 1.2-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-4-((phenylamino)methyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(Example 1, Step 4, 200 mg, 0.343 mmol) in DCM (4 mL) was added aniline(96 mg, 1.030 mmol) and acetic acid (98 μL, 1.716 mmol). The reactionmixture was then stirred at r.t. for 1 hour before sodiumcyanoborohydride (64.7 mg, 1.030 mmol) was added. The solution was thenstirred at r.t. for 1 hour, diluted with DCM, and washed with NaHCO₃solution and brine. The organic layer was dried over MgSO₄, filtered,and then concentrated to dryness. The residue was washed through a shortsilica gel column using 30% methanol in DCM. The obtained intermediatewas dissolved in THE (4.00 mL) and EtOH (4.00 mL) then iron (96 mg,1.716 mmol) and HCl (515 μL, 0.515 mmol) were added, and the resultingmixture was stirred at 80° C. for 1 hour. After this time, the mixturewas cooled to r.t., diluted with 1:1 DCM and MeOH, then stirred for anadditional 20 minutes before being filtered. The filtrate wasconcentrated to dryness then purified by silica gel chromatography using0-60% methanol in DCM. LC-MS calculated for C₃₃H₃₆N₅O₄S₂ (M+H)⁺:m/z=630.2; found 630.2.

Step 2.8-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-4-((phenylamino)methyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine(104 mg, 0.165 mmol) in THE (3 mL) was added triethylamine (46.0 μL,0.330 mmol) and triphosgene (24.50 mg, 0.083 mmol), and the resultingmixture was stirred at r.t. for 15 minutes. After this time, the mixturewas quenched with water and then extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered, andthen concentrated to dryness to afford desired product. LC-MS calculatedfor C₃₄H₃₄N₅O₅S₂(M+H)⁺: m/z=656.2; found 656.2.

Step 3.4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of8-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-onein DMF (2.00 mL) was added iodomethane (10.33 μL, 0.165 mmol). Sodiumhydride (7.93 mg, 0.198 mmol) was added and the resulting mixture wasstirred at r.t. for 10 minutes. After this time, the reaction wasquenched with water and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over MgSO₄, filtered, andthen concentrated to dryness. The resulting residue was suspended in 1:1MeOH and 2.5M NaOH solution then stirred at 80° C. for 1 hour. Afterthis time, the pH was adjusted to 1 then the mixture was diluted withmethanol, filtered, and then purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to afford the title compound. LC-MS calculatedfor C₂₉H₃₂N₅O₃S (M+H)⁺: m/z=530.2; found 530.2.

Example 3.4-(4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid

The title compound was prepared according to the procedures described inExample 2, using methyl 4-aminobenzoate instead of aniline as startingmaterial in Step 1. LC-MS calculated for C₃₀H₃₂N₅O₅S (M+H)⁺: m/z=574.2;found 574.2.

Example 4.8-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-(pyridin-3-ylmethyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

Step 1.5-Amino-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(Example 1, Step 4, 500 mg, 0.858 mmol) in THE (3 mL), MeOH (3.00 mL)and water, (3.00 mL) was added iron (240 mg, 4.29 mmol) and ammoniumchloride (230 mg, 4.29 mmol) and the resulting mixture was stirred at60° C. for 2 hours. After this time, the mixture was cooled to r.t.,filtered, and then concentrated to dryness. The residue was purified bysilica gel chromatography using 0-30% methanol in DCM to afford desiredproduct as brownish oil (0.21 g, 44.3%). LC-MS calculated forC₂₇H₂₉N₄O₅S₂ (M+H)⁺: m/z=553.2; found 553.1.

Step 2.8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-(pyridin-3-ylmethyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of5-amino-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(50 mg, 0.090 mmol) in MeOH (1 mL) and THE (0.5 mL) was addedpyridin-3-ylmethanamine (98 mg, 0.91 mmol), and the resulting mixturewas stirred at r.t. for 15 hours. After this time, sodium borohydride(17.11 mg, 0.452 mmol) was added. Additional sodium borohydride was thenadded until all imine was consumed. The resulting mixture was dilutedwith ethyl acetate and then washed with water and brine. The aqueouslayer was extracted with ethyl acetate and then washed with brine. Thecombined organic layer was dried over MgSO₄, filtered, and thenconcentrated to dryness. The resulting residue was dissolved in THE (1.0mL), then CDI (44.0 mg, 0.271 mmol) was added in one portion and theresulting mixture was stirred at r.t. for 30 minutes. After this time,the mixture was diluted with 1 mL MeOH and 1 mL 2.5M NaOH, then stirredat 60° C. for 2 hours. After this time, the mixture was cooled to r.t.,the pH was adjusted to 1, and the residue purified by prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to afford the title compound. LC-MScalculated for C₂₈H₃₁N₆O₃S (M+H)⁺: m/z=531.2; found 531.1.

Example 5.2-Cyclohexyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

Step 1.4-((Cyclohexylamino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(Example 1, Step 4, 50 mg, 0.086 mmol) in DCM (1 mL) was added aceticacid (24.56 μL, 0.429 mmol) and cyclohexanamine (25.5 mg, 0.257 mmol),and the resulting mixture was stirred for 3 hours at r.t. After thistime, sodium cyanoborohydride (27.0 mg, 0.429 mmol) was added and thereaction mixture was stirred for an additional 1 hour at r.t. After thistime, the reaction mixture was diluted with DCM then washed with waterand aqueous NaHCO₃ solution. The organic layer was dried over MgSO₄,filtered, and then concentrated to dryness. The resulting residue wasthen dissolved in MeOH (1.0 mL) and THE (1.0 mL), then Pd on carbon (10mg) was added and the mixture was stirred under H₂ atmosphere at 60° C.for 1 hour. After this time, the reaction mixture was filtered, thendiluted with methanol, and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to afford the title compound. LC-MS calculatedfor C₃₃H₄₂N₅O₄S₂(M+H)⁺: m/z=635.2; found 635.1.

Step 2.2-Cyclohexyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The4-((cyclohexylamino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amineobtained from Step 1 was dissolved in THF, then CDI (44.0 mg, 0.271mmol) was added and the resulting mixture was stirred at r.t. for 2hours. After this time, the mixture was diluted with 1 mL 2.5M NaOHsolution then stirred at 60° C. for 1 hour. After this time, the mixturewas diluted with methanol, filtered, and then purified by prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to afford the titlecompound. LC-MS calculated for C₂₈H₃₆N₅O₃S (M+H)⁺: m/z=522.2; found522.1.

Examples 6-7

Examples 6-7 of Table 2 were prepared according to the proceduresdescribed in Example 4.

TABLE 2

Ex. LCMS No. Name R [M + H]⁺ 6 4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)cyclohexane-1-carboxylic acid

566.2 7 4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)piperidine-1-sulfonamide

602.2

Example 8.2-(4-((2-Methoxyethyl)amino)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

Step 1.4-(((4-Bromophenyl)amino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

To a solution of2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(Example 1, Step 4, 1800 mg, 3.09 mmol) in DCM (36 mL) was added4-bromoaniline (1594 mg, 9.27 mmol) and acetic acid (884 μL, 15.45mmol), and the resulting mixture was stirred at r.t. for 1 hour. Next,sodium cyanoborohydride (582 mg, 9.27 mmol) was added and the mixturewas stirred at r.t. for 1 hour. The mixture was then diluted with DCMand washed with NaHCO₃ solution and brine. The organic layer was driedover MgSO₄, filtered, and then concentrated to dryness. The residue wasdissolved in THE (10.0 mL), water (10.0 mL), and MeOH (10 mL). To theresulting suspension was added iron (863 mg, 15.45 mmol) and ammoniumchloride (826 mg, 15.45 mmol), and the mixture was stirred at 80° C. for2 hours. After this time, the mixture was cooled to r.t., filtered, andconcentrated to dryness. The resulting residue was purified by silicagel chromatography using 0-50% methanol in DCM to afford desired productas brownish oil (1.32 g, 60.3%). LC-MS calculated for C₃₃H₃₅BrN₅O₄S₂(M+H)⁺: m/z=708.0; found 708.0.

Step 2.2-(4-Bromophenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of4-(((4-bromophenyl)amino)methyl)-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine(1.2 g, 1.693 mmol) in THE (40 mL) was added triethylamine (0.708 mL,5.08 mmol) and triphosgene (0.251 g, 0.847 mmol), and the resultingmixture was stirred at r.t. for 30 minutes. After this time, thereaction was quenched with NaOH solution, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overMgSO₄, filtered, and then concentrated to dryness. The resulting residuewas then dissolved in DMF (10.0 mL) and iodomethane (0.159 mL, 2.54mmol). Sodium hydride (0.102 g, 2.54 mmol) was added and the resultingmixture was stirred at r.t. for 30 minutes. After this time, thereaction was quenched with water and the mixture was extracted withethyl acetate. The organic layer was washed with brine, dried overMgSO₄, filtered, and then concentrated to dryness. The residue waspurified by silica gel chromatography using 0-10% methanol in DCM toafford desired product as brownish oil (704 mg, 55.5%). LC-MS calculatedfor C₃₅H₃₄BrN₅O₅S₂ (M+H)⁺: m/z=748.0; found 748.0.

Step 3.2-(4-((2-Methoxyethyl)amino)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of2-(4-bromophenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one(25 mg, 0.033 mmol) in dioxane (1 mL) was added 2-methoxyethan-1-amine(7.52 mg, 0.100 mmol),[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (tBuBrettPhos Pd G3, 8.56 mg, 10.02 μmol) and cesiumcarbonate (32.6 mg, 0.100 mmol). N₂ was then bubbled through the mixturefor 1 minute, then the mixture was heated at 100° C. and stirred for 15hours at 100° C. After this time, the mixture was cooled to r.t.,diluted with methanol and 2.5M NaOH solution, and then stirred at 60° C.for 1 hour. The resulting solution was diluted with methanol and water,filtered, and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% NH₄OH, at flow rate of 60mL/min) to afford the title compound. LC-MS calculated for C₃₂H₃₉N₆O₄S(M+H)⁺: m/z=603.2; found 603.1.

Example 9.2-Cyano-N-(4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)phenyl)acetamide

The title compound was prepared according to the procedures described inExample 8, using 2-methoxyethan-1-amine instead of aniline as startingmaterial in Step 3. LC-MS calculated for C₃₂H₃₄N₇O₄S (M+H)⁺: m/z=612.2;found 612.2.

Example 10.4-(1,4-Dimethyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid

Step 1.4-Chloro-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of2-bromo-4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(Example 1, Step 2, 2.5 g, 6.00 mmol) and4-(methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine(Example 1, Step 1, 1.366 g, 3.60 mmol) in dioxane (50 mL) and water(12.50 mL) was added cesium carbonate (7.82 g, 24.00 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.980 g,1.20 mmol). N₂ was bubbled through the mixture for 5 minutes then themixture was stirred at 70° C. for 2 hours. The resulting solution wasthen cooled to r.t. and water was removed. The resulting mixture wasconcentrated to dryness and then purified by silica gel chromatographyusing 0-5% methanol in dichloromethane with 1% triethylamine as additiveto afford desired product as brownish oil (1.40 g, 2.38 mmol). LC-MScalculated for C₂₈H₂₉N₄O₆S₂ (M+H)⁺: m/z=589.2; found 589.2.

Step 2.1-(2-(4-((4-(Methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethan-1-one

To a solution of4-chloro-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(1600 mg, 2.72 mmol) in dioxane (20 mL) was added1-ethoxyvinyltri-n-butyltin (1101 μL, 3.26 mmol) and triphenylphosphinepalladium chloride (381 mg, 0.543 mmol), and the resulting mixture wasstirred at 100° C. for 2 hours. After this time, the mixture was cooledto r.t. then water (2 mL) and concentrated hydrochloric acid (2 mL) wereadded and the resulting mixture was stirred for 1 hour at r.t. Afterthis time, the pH was adjusted to 7, the mixture was diluted with water,and extracted with dichloromethane. The organic layer was dried overMgSO₄, filtered, and then concentrated to dryness. The residue waspurified by silica gel chromatography using 0-10% methanol in DCM with1% TEA as additive to afford desired product (1.33 g, 2.23 mmol). LC-MScalculated for C₂₈H₂₉N₄O₇S₂ (M+H)⁺: m/z=597.2; found 597.2.

Step 3. Methyl4-((1-(5-amino-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl)amino)benzoate

To a solution of1-(2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethan-1-one(400 mg, 0.670 mmol) in DCM (5 mL) was added methyl 4-aminobenzoate (304mg, 2.011 mmol) and titanium tetrachloride (1006 μL, 1.006 mmol), andthe resulting mixture was stirred at r.t. for 1 hour. Next, a solutionof sodium cyanoborohydride (211 mg, 3.35 mmol) in MeOH (1.00 mL) wasadded. The reaction mixture was stirred at r.t. for 1 hour then dilutedwith NaOH 1N solution, filtered, and then extracted with DCM. Theorganic layer was washed with water, dried over MgSO₄, filtered, andthen concentrated to dryness. The residue was dissolved in THF (1 mL),MeOH (1.00 mL), and water (1.00 mL). To the resulting suspension wasadded iron (187 mg, 3.35 mmol) and ammonium chloride (179 mg, 3.35mmol), and the resulting mixture was stirred at 80° C. for 90 minutes.After this time, the mixture was cooled to r.t., diluted with methanol,filtered, and then concentrated to dryness. The resulting residue waspurified by silica gel chromatography using 0-30% methanol in DCM with1% TEA as additive to afford desired product as brownish oil (164 mg,34.9%). LC-MS calculated for C₃₆H₄₀N₅O₆S₂(M+H)⁺: m/z=702.2; found 702.2.

Step 4.4-(1,4-Dimethyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid

To a solution of methyl4-((1-(5-amino-2-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)ethyl)amino)benzoate(100 mg, 0.142 mmol) in THE (2.85 mL) was added triethylamine (59.6 μL,0.427 mmol) and triphosgene (21.14 mg, 0.071 mmol), and the resultingmixture was stirred at r.t. for 10 minutes. After this time, the mixturewas quenched with 1N NaOH then extracted with DCM. The organic layer wasconcentrated to dryness and the resulting residue was dissolved in 1 mLDMF. Iodomethane (13.36 μL, 0.214 mmol) was added followed by additionof sodium hydride (8.55 mg, 0.214 mmol). The resulting solution was thenstirred at r.t. for 30 minutes, quenched with water, and extracted withethyl acetate. The resulting solution was then concentrated to dryness,then dissolved in 1:1 1N NaOH and methanol and stirred at 80° C. for 1hour. After this time, the mixture was cooled to r.t., diluted withmethanol, and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% NH₄OH, at flow rate of 60mL/min) to afford the title compound as a racemic mixture. LC-MScalculated for C₃₁H₃₄N₅O₅S (M+H)⁺: m/z=588.2; found 588.1. ¹H NMR (600MHz, DMSO-d6) δ 12.16 (s, 1H), 8.11 (s, 1H), 7.98-7.93 (m, 2H), 7.89 (d,J=8.0 Hz, 2H), 7.52-7.46 (m, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.08 (s, 1H),5.49-5.37 (m, 1H), 3.52 (s, 2H), 3.44 (s, 3H), 3.10-3.01 (m, 1H), 2.96(dt, J=12.5, 3.3 Hz, 2H), 2.92 (s, 3H), 2.04-1.96 (m, 4H), 1.63 (qd,J=12.2, 3.9 Hz, 2H), 1.49 (d, J=6.5 Hz, 3H).

Example 11.4-(9-(4-Methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-(pyridin-3-yl)benzamide,Bistrifluoroacetic Acid Salt

Step 1. 5-Nitro-1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine

A mixture of4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (7.00 g,20.7 mmol) (Enamine) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(4.79 g, 31.1 mmol) in 1,4-dioxane (72 mL) and water (22 mL) was treatedwith tribasic potassium phosphate (13.2 g, 62.2 mmol) and degassed withnitrogen for 15 min. The reaction mixture was treated withdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (XPhos Pd G2) (1.63 g, 2.07 mmol), degassed with nitrogen for 15min, and stirred at 70° C. for 2.5 h. The reaction mixture was thendiluted with ethyl acetate (70 mL) and water (30 mL) and filteredthrough Celite. The aqueous layer was separated and extracted with ethylacetate (2×50 mL). The combined organic extracts were washed withsaturated sodium chloride solution, dried over magnesium sulfate,filtered, and concentrated to a brown solid. The solid was suspended inmethanol (35 mL) and stirred for 2 h. The solid was isolated byfiltration, washed with methanol (3×5 mL), and dried under high vacuumto afford the desired product (6.16 g, 90.2%) as a brown solid. LCMS forC₁₅H₁₂N₃O₄S (M+H)⁺: m/z=330.1; Found: 330.0.

Step 2.5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of5-nitro-1-(phenylsulfonyl)-4-vinyl-1H-pyrrolo[2,3-b]pyridine (6.16 g,18.7 mmol) in THE (130 mL) was added water (26.0 mL) and potassiumosmate dihydrate (0.138 g, 0.374 mmol). Sodium periodate (12.0 g, 56.1mmol) was then added and the resulting mixture was stirred for 22 h. Thereaction mixture was diluted with dichloromethane (200 mL) and water(200 mL), and the organic layer was collected. Additionaldichloromethane and 20% sodium thiosulfate solution was added to theaqueous layer, and the organic layer was collected. The aqueous layerwas then back-extracted with dichloromethane. The combined extracts werewashed with 20% sodium thiosulfate solution and brine, dried overmagnesium sulfate, filtered, and concentrated to give the desiredproduct (5.64 g, 91.1% yield) as a brown solid. LCMS for C₁₄H₁₀N₃O₅S(M+H)⁺: m/z=332.0; Found: 332.0.

Step 3. tert-Butyl4-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate

To a solution of5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(5.64 g, 17.0 mmol) and tert-butyl 4-aminobenzoate (3.29 g, 17.0 mmol)in dichloromethane (155 mL) was added acetic acid (0.975 mL, 17.0 mmol).The resulting mixture was stirred for 64 h and was cooled to 0° C.Sodium cyanoborohydride (1.28 g, 20.4 mmol) was added, the cooling bathwas removed, and the reaction mixture was stirred for 1 h, at which timeadditional sodium cyanoborohydride (0.267 g, 4.26 mmol) was added. Themixture was stirred for an additional 30 min, then cooled with ice,diluted with 200 mL of saturated sodium bicarbonate solution, and warmedto ambient temperature. The resulting solids were filtered, the filtratewere separated, and the aqueous layer was extracted with dichloromethane(2×150 mL). The combined dichloromethane extracts were washed withsaturated sodium chloride solution, dried over sodium sulfate, filtered,and concentrated to give a brown foam. Purification by flash columnchromatography using ethyl acetate in hexanes (0% to 100%) afforded thedesired product (4.91 g, 56.7%) as a yellow foam. LC/MS for C₂₅H₂₅N₄O₆S(M+H)⁺: m/z=509.1; Found: 509.2.

Step 4. tert-Butyl4-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate

To a mixture of tert-butyl4-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate(4.75 g, 9.35 mmol) and iron (3.68 g, 65.9 mmol) in methanol (31.8 mL),THE (31.8 mL), and water (31.8 mL) was added ammonium chloride (3.66 g,68.4 mmol). The resulting mixture was refluxed at 70° C. for 2 h. Themixture was diluted with saturated sodium chloride solution (50 mL) andethyl acetate (50 mL), then filtered through Celite. The Celite waswashed with EtOAc (200 mL). The filtrate was transferred to a separatoryfunnel with saturated sodium chloride solution (50 mL) and the layerswere separated. The ethyl acetate layer was dried over sodium sulfate,filtered, and concentrated to afford the desired product (4.62 g, >100%)as a yellow foam. Assumed 100% yield and carried on to step 5. LCMS forC₂₅H₂₇N₄O₄S (M+H)⁺: m/z=479.2; Found: 479.2.

Step 5. tert-Butyl4-(3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

To a suspension of tert-butyl4-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate(4.47 g, 9.34 mmol) in THE (46.7 mL) was added carbonyldiimidazole (7.57g, 46.7 mmol). The resulting suspension was stirred at ambienttemperature for 18 h. The suspension was cooled with ice while water(125 mL) was added dropwise to quench any excess carbonyldiimidazole.The suspension was filtered and the tan solid was washed with water(3×30 mL). The solid was concentrated from acetonitrile (2×) to providethe desired product (4.28 g, 90.9%) as a tan solid. LCMS for C₂₆H₂₅N₄O₅S(M+H)⁺: m/z=505.2; Found: 505.1.

Step 6. tert-Butyl4-(4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

To a suspension of tert-butyl4-(3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(3.30 g, 6.54 mmol) in DMF (32.7 mL) and THE (32.7 mL) was added cesiumcarbonate (6.39 g, 19.6 mmol) and methyl iodide (2.86 mL, 45.8 mmol).The resulting suspension was stirred for 1.5 h. The suspension wasdiluted with ethyl acetate (200 mL) and water (200 mL). The layers wereseparated, and the ethyl acetate layer was washed with saturated sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedto an orange solid. Purification by flash column chromatography usingmethanol in dichloromethane (0% to 10%) gave the desired product (3.39g, 100%) as a tan solid. LCMS for C₂₇H₂₇N₄O₅S (M+H)⁺: m/z=519.2; Found:519.2.

Step 7. tert-Butyl4-(8-bromo-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

To a solution of tert-butyl4-(4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(2.71 g, 5.22 mmol) in THE (35 mL) at −78° C. was added LDA (2M solutionin THE/heptane/ethylbenzene, 3.92 mL, 7.83 mmol). The resulting mixturewas stirred at −78° C. for 1.5 min, a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (2.55 g, 7.83 mmol) in THE (7.00mL) was added, and the resulting mixture was stirred at −78° C. for 1 h.Saturated ammonium chloride solution was added dropwise at −78° C. andthe reaction mixture was warmed to ambient temperature. The mixture wasdiluted with ethyl acetate (200 mL) and water (100 mL). The layers wereseparated and the ethyl acetate layer was washed with saturated sodiumchloride solution, dried over sodium sulfate, filtered, and concentratedto a tan foam. Purification by flash column chromatography using ethylacetate (containing 5% methanol) in hexanes (0-75%) gave the desiredproduct (3.12 g, 61.5%) as a tan solid. LCMS for C₂₇H₂₆BrN₄O₅S (M+H)⁺:m/z=597.1, 599.1; Found: 597.1, 599.1.

Step 8. tert-Butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

A mixture of tert-butyl4-(8-bromo-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(2.16 g, 3.62 mmol),4-(methylsulfonyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidine(1.65 g, 4.35 mmol), and cesium fluoride (2.75 g, 18.1 mmol) in1,4-dioxane (45 mL) and water (6.00 mL) was degassed by bubbling withnitrogen for 10 min.Dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (0.274g, 0.362 mmol) (Pd127) was added and the mixture was degassed withnitrogen for 10 min, then refluxed at 110° C. for 8.5 h. The reactionmixture was diluted with EtOAc (50 mL) and filtered through a 0.45micron filter cartridge. The filtrate was diluted with ethyl acetate(100 mL) and water (20 mL) and the layers were separated. The ethylacetate layer was washed with saturated sodium chloride solution, driedover sodium sulfate, filtered, and concentrated to a dark brown foam.Purification by flash column chromatography using ethyl acetate(containing 5% methanol) in hexanes (0-100%) gave the desired product(2.07 g, 74.2%) as a rust colored foam. LCMS for C₄₀H₄₄N₅O₇S₂(M+H)⁺:m/z=770.3; Found: 770.4.

Step 9. tert-Butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

To a solution of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(2.02 g, 2.62 mmol) in THE (17.5 mL) and methanol (17.5 mL) at 0° C. wasadded a 3 M solution of potassium hydroxide (17.5 mL, 52.4 mmol) inwater. The ice bath was removed and the thick suspension was stirred for2 h. THE (15 mL) was added which dissolved some of the solids andproduced a finer suspension. The reaction mixture was stirred for anadditional 2 h, THE (5 mL) was added to dissolve all solids and themixture was stirred for an additional 2.5 h. The mixture was dilutedwith dichloromethane (100 mL) and water (100 mL) and stirred until allsolids dissolved. The mixture was transferred to a separatory funnel andthe layers were separated. The aqueous layer was extracted withdichloromethane (100 mL) and the combined dichloromethane extracts weredried over sodium sulfate, filtered, and concentrated to afford thedesired product (1.32 g, 80.0%) as a tan solid. LCMS for C₃₄H₄₀N₅O₅S(M+H)⁺: m/z=630.3; Found: 630.3.

Step 10. tert-Butyl4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

A suspension of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(1.32 g, 2.10 mmol) in THE (52.4 mL) was evacuated and refilled withnitrogen six times. NIS (0.707 g, 3.14 mmol) was added and the flask wasevacuated and refilled with nitrogen six more times. The resultingsuspension slowly became a solution after NIS addition. The mixture wasstirred for 30 min and, while still under nitrogen, diluted with asolution of 10% sodium thiosulfate in water (20 mL) and ethyl acetate(100 mL). The mixture was stirred for 15 min under nitrogen, transferredto a separatory funnel with EtOAc (20 mL), and the layers wereseparated. The ethyl acetate layer was washed with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The ethylacetate layer was then dried over sodium sulfate, filtered, andconcentrated to provide the desired product (1.56 g, 98.5%) as abrown/orange solid. LCMS for C₃₄H₃₉IN₅O₅S (M+H)⁺: m/z=756.2; Found:756.2.

Step 11. tert-Butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate

To a solution of tert-butyl4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(1.56 g, 2.06 mmol) in dichloromethane (27.4 mL) was added di-tert-butyldicarbonate (1.35 g, 6.17 mmol) and 4-dimethylaminopyridine (0.126 g,1.03 mmol). The mixture was stirred at ambient temperature for 1.5 h andwas diluted with dichloromethane (100 mL). A mixture of water (50mL)/saturated sodium bicarbonate solution (50 mL) was added and thelayers were separated. The aqueous layer was extracted with additionaldichloromethane (50 mL). The combined dichloromethane extracts werewashed with saturated sodium chloride solution, dried over sodiumsulfate, filtered, and concentrated to a brown foam. Purification byflash column chromatography using methanol in dichloromethane (0-10%)afforded the desired product (1.51 g, 86.0%) as a tan foam. LCMS forC₃₉H₄₇IN₅O₇S (M+H)⁺: m/z=856.2; Found: 856.1.

Step 12. tert-Butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate

A solution of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(0.166 g, 0.194 mmol) and (4-methoxyphenyl)boronic acid (0.088 g, 0.582mmol) in 1,4-dioxane (2.8 mL) was treated with a 1.0 M solution ofpotassium carbonate (0.970 mL, 0.970 mmol) in water. The mixture wasbubbled with nitrogen for 5 min and was treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.024 g, 0.029 mmol). The mixture was bubbledwith nitrogen for an additional 5 min and heated at 80° C. for 1.5 h.The reaction mixture was diluted with ethyl acetate (40 mL), filteredthrough a 0.45 micron filter cartridge, and the solids were rinsed withadditional ethyl acetate (10 mL). The filtrate was washed with saturatedsodium chloride solution (10 mL), dried over sodium sulfate, filtered,and concentrated to an orange foam. Purification by flash columnchromatography using ethyl acetate (containing 5% methanol) in hexanes(0-100%) afforded the desired product (0.141 g, 87.0%) as a slightly tansolid. LCMS for C₄₆H₅₄N₅O₈S (M+H)⁺: m/z=836.4; Found: 836.5.

Step 13.4-(9-(4-Methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

To a solution of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(0.141 g, 0.169 mmol) in dichloromethane (1.69 mL) was addedtrifluoroacetic acid (1.69 mL, 21.9 mmol), dropwise, and the resultingsolution was stirred for 1.5 h. The solution was concentrated andreconcentrated from acetonitrile (4×) to provide the desired product(0.145 g, >100%) as a brown solid, which was used in the next stepwithout further purification. LCMS for C₃₇H₃₈N₅O₆S (M+H)⁺: m/z=680.3;Found: 680.3.

Step 14.4-(9-(4-Methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-(pyridin-3-yl)benzamideBistrifluoroacetic Acid Salt

A solution of4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid, trifluoroacetic acid salt (0.006 g, 7.56 μmol) and triethylamine(10.5 μL, 0.076 mmol) in N,N-dimethylformamide (0.300 mL) was treatedwith 3-aminopyridine (3.56 mg, 0.038 mmol) and HATU (4.31 mg, 0.011mmol). The resulting mixture was stirred for 3 h. The reaction mixturewas diluted with acetonitrile and water and was acidified withtrifluoroacetic acid. The solution was purified via preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to afford thedesired product (3.4 mg, 45.7%) as a yellow tinted solid. LCMS forC₄₂H₄₂N₇O₅S (M+H)⁺: m/z=756.3; Found: 756.3.

Example 12

Example 12 of Table 3 was prepared according to the procedures describedin Example 11.

TABLE 3

Ex. LCMS ¹H NMR No. Name R₁ R₂ [M + H]⁺ Spectrum 12 4-(9-(4-methoxyphenyl)- 4-methyl-8-(4-((4-

H 693.3 ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.44-(methylsulfonyl) 9.39 (m, 1H), piperidin-1- 8.42-8.35 (m,yl)methyl)phenyl)- 1H), 8.19 (s, 1H), 3-oxo-1,3,4,7- 7.74 (d, J = 8.5Hz, tetrahydro-2H- 2H), 7.57 (d, J = pyrrolo[3′,2′:5,6] 8.0 Hz, 2H),7.44 pyrido[3,4- (d, J = 8.0 Hz, 2H), d]pyrimidin-2-yl)- 7.29 (d, J =8.5 Hz, N- 2H), 7.11 (d, J = methylbenzamide, 8.6 Hz, 2H), 7.00trifluroacetate (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 4.31- 4.25 (m, 2H),3.82 (s, 3H), 3.52 (d, J = 12.1 Hz, 2H), 3.45- 3.32 (m, 4H), 3.05-2.90(m, 5H), 2.81-2.76 (m, 3H), 2.24 (d, J = 13.8 Hz, 2H), 1.91-1.77 (m,2H).

Example 13.N-(2-(2-Benzylhydrazineyl)-2-oxoethyl)-4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzamide, TFA

Step 1. tert-Butyl(4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoyl)glycinate

The title compound was prepared according to the procedures described inExample 11, Step 14, using tert-butyl glycinate in place of3-aminopyridine as the starting material. LCMS for C₄₃H₄₉N₆O₇S (M+H)⁺:m/z=793.3; Found: 793.3.

Step 2.(4-(9-(4-Methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoyl)glycineTrifluoroacetic Acid Salt

The title compound was prepared according to the procedures described inExample 11, Step 13, using tert-butyl(4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoyl)glycinatein place of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylateas the starting material. LCMS for C₃₉H₄₁N₆O₇S (M+H)⁺: m/z=737.3; Found:737.3.

Step 3. tert-Butyl 1-benzylhydrazine-1-carboxylate

A solution of benzylhydrazine, 2HCl (0.350 g, 1.79 mmol) in THE (8.97mL) was treated with Boc-anhydride (0.458 mL, 1.97 mmol) followed bydropwise addition of a solution of sodium bicarbonate (0.603 g, 7.18mmol) in water (4.69 mL, 260 mmol), and the resulting mixture wasstirred for 14 h. The reaction mixture was diluted with EtOAc (50 mL),water (10 mL), and sat. NaHCO₃ solution (20 mL). The organic layer wasseparated and washed with sat. NaCl solution, dried over anhydroussodium sulfate, filtered, and concentrated to a tan oil. Purification byflash column chromatography using MTBE in hexanes (0-100%) afforded thedesired product (384 mg, 96.2%) as a colorless oil containing ˜10% oftert-butyl 2-benzylhydrazine-1-carboxylate. The product was furtherpurified by preparative LCMS (XBridge® C18 column, eluting with agradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of60 mL/min) to remove the tert-butyl 2-benzylhydrazine-1-carboxylate.LCMS for C₈H₁₁N₂O₂(M+H)⁺: m/z=167.2; Found: 167.1.

Step 4.N-(2-(2-Benzylhydrazineyl)-2-oxoethyl)-4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzamideTrifluoroacetic Acid Salt

The title compound was prepared according to the procedure described inExample 11, Step 14, using(4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoyl)glycinetrifluoroacetic acid in place of4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid, trifluoroacetic acid salt and tert-butyl1-benzylhydrazine-1-carboxylate in place of 3-aminopyridine as thestarting materials. LCMS for C₄₆H₄₉N₈O₆S (M+H)⁺: m/z=841.3; Found:841.3.

Example 14.4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-((1-cyanocyclopropyl)methyl)benzamideTrifluoroacetic Acid

Step 1.2-Methyl-N-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)propan-2-amine

The title compound was prepared according to the procedures described inExample #11, Step 3, using tert-butylamine as the starting material inplace of tert-butyl 4-aminobenzoate. LCMS for C₁₈H₂₁N₄O₄S (M+H)⁺:m/z=389.1; Found: 389.1.

Step 2.4-((tert-Butylamino)methyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

The title compound was prepared according to the procedures described inExample 11, Step 4, using2-methyl-N-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)propan-2-amineas the starting material in place of tert-butyl4-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate.LCMS for C₁₈H₂₃N₄O₂S (M+H)⁺: m/z=359.2; Found: 359.1.

Step 3.2-(tert-Butyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The title compound was prepared according to the procedures described inExample 11, Step 5, using4-((tert-butylamino)methyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amineas the starting material in place of tert-butyl4-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)benzoate.LCMS for C₁₉H₂₁N₄O₃S (M+H)⁺: m/z=385.1; Found: 385.1.

Step 4.2-(tert-Butyl)-4-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The title compound was prepared according to the procedures described inExample 11, Step 6, using2-(tert-butyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-oneas the starting material in place of tert-butyl4-(3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate.LCMS for C₂₀H₂₃N₄O₃S (M+H)⁺: m/z=399.1; Found: 399.1.

Step 5.8-Bromo-2-(tert-butyl)-4-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The title compound was prepared according to the procedures described inExample 11, Step 7, using2-(tert-butyl)-4-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-oneas the starting material in place of tert-butyl4-(4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate.LCMS for C₂₀H₂₂BrN₄O₃S (M+H)⁺: m/z=477.1, 479.1; Found: 477.0, 479.1.

Step 6.2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The title compound was prepared according to the procedures described inExample 11, Step 8, using8-bromo-2-(tert-butyl)-4-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-oneas the starting material in place of tert-butyl4-(8-bromo-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate.LCMS for C₃₃H₄₀N₅O₅S₂ (M+H)⁺: m/z=650.2; Found: 650.3.

Step 7.2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

The title compound was prepared according to the procedures described inExample 11, Step 9, using2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-oneas the starting material in place of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate.LCMS for C₂₇H₃₆N₅O₃S (M+H)⁺: m/z=510.3; Found: 510.3.

Step 8.2-(tert-Butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one

To a solution of2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one(0.238 g, 0.467 mmol) and N,N-diisopropylethylamine (0.245 mL, 1.401mmol) in DMF (3.11 mL) was added NIS (0.158 g, 0.700 mmol). The reactionmixture was stirred at room temperature for 40 minutes, then additionalNIS (0.026 g, 0.25 eq) was added. The mixture was stirred at roomtemperature for 1 h. 10% Sodium bisulfate was added to reaction mixture,followed by deionized water, sat. aq. sodium bicarbonate solution, andethyl acetate. The product was extracted with ethyl acetate (3×). Thecombined extracts were washed with brine, then dried over magnesiumsulfate, filtered, and concentrated to a brown solid. Methanol (5.0 mL)was added and the resulting mixture was stirred for 3 h. The solids wereisolated by filtration and washed with methanol (2×2.0 mL). Air waspulled through the solids for 15 min and the solids were placed on highvacuum for 2 h to afford the desired product (181 mg, 60.9%) as a lighttan solid. LCMS for C₂₇H₃₅IN₅O₃S (M+H)⁺: m/z=636.1; Found: 636.1.

Step 9. tert-Butyl2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate

The title compound was prepared according to the procedures described inExample 11, Step 11, using2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-oneas the starting material in place of tert-butyl4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate.LCMS for C₃₂H₄₃IN₅O₅S (M+H)⁺: m/z=736.2; Found: 736.3.

Step 10. tert-Butyl2-(tert-butyl)-9-(4-(methoxycarbonyl)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate

A vial containingdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (3.33 mg, 4.08 μmol) and methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.014 g, 0.054mmol) was charged with a solution of tert-butyl2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(0.020 g, 0.027 mmol) in 1,4-dioxane (0.544 mL), followed by 1.0 Mpotassium carbonate in water (0.082 mL, 0.082 mmol). The mixture wasbubbled with nitrogen for 5 min and the sealed vial was heated at 80° C.for 6 h. The reaction mixture was diluted with ethyl acetate andfiltered through a 0.45 micron filter cartridge. The solids were rinsedwith ethyl acetate and the filtrate was concentrated to a brown oil.Purification by flash column chromatography using ethyl acetate(containing 5% methanol) in hexanes (0% to 100%) afforded the desiredproduct (15 mg, 74.3%) as a brown oil. LCMS for C₄₀H₅₀N₅O₇S (M+H)⁺:m/z=744.3; Found: 744.4.

Step 11.4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzoicacid

A solution of tert-butyl2-(tert-butyl)-9-(4-(methoxycarbonyl)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(15 mg, 0.020 mmol) in dry THE (0.50 mL) was treated with sodiummethoxide (25 wt % in methanol, 0.025 mL, 0.109 mmol). The mixture wasstirred at room temp for 40 min. Methanol (0.5 mL) was added to reactionmixture, followed by sodium hydroxide (1.0 N in water, 0.136 mL, 0.136mmol) and the resulting mixture was stirred at room temp for 18 h. 1 NHCl (˜0.3 mL) was added, bringing reaction mixture to pH 5-6. Themixture was then concentrated and placed on high vacuum overnight toafford the desired product (30 mg) as an impure tan solid that containedinorganic salts. LCMS for C₃₄H₄₀N₅O₅S (M+H)⁺: m/z=630.3; Found: 630.3.

Step 12.4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-((1-cyanocyclopropyl)methyl)benzamideTrifluoroacetic Acid Salt

A mixture of4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzoicacid (9.9 mg, 42.3 wt %, 6.67 μmol),1-(aminomethyl)cyclopropane-1-carbonitrile, hydrochloride (2.65 mg,0.020 mmol), and HATU (3.80 mg, 10.00 μmol) in DMF (0.167 mL) wastreated with triethylamine (5.58 μL, 0.040 mmol). The reaction mixturewas stirred at room temperature for 40 minutes, then methanol anddeionized water were added to the reaction mixture. The resultingsolution was purified via preparative LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.1% trifluoroacetic acid,at flow rate of 60 mL/min) to afford the desired product (2.8 mg, 51.1%)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.41 (s,1H), 8.99 (s, 1H), 8.07 (s, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.57-7.49 (m,4H), 7.45 (d, J=8.1 Hz, 2H), 4.28 (s, 2H), 4.02 (s, 2H), 3.28 (s, 3H),2.99 (s, 3H), 2.24 (d, J=13.8 Hz, 2H), 1.84 (d, J=13.3 Hz, 2H),1.28-1.22 (m, 2H), 1.16 (t, J=3.4 Hz, 2H), 1.10 (s, 9H). LCMS forC₃₉H₄₆N₇O₄S (M+H)⁺: m/z=708.3; Found: 708.3.

Example 15.4-(9-(Methoxycarbonyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

A solution of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(Example 11, Step 11, 0.008 g, 9.35 μmol), triethylamine (6.51 μL, 0.047mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (1.145 mg, 1.402 μmol) in methanol (0.234 mL) wasbubbled with nitrogen for 5 min and then bubbled with carbon monoxidefor 5 min. The reaction mixture was stirred at 65° C. overnight, cooledto RT, and diluted with ethyl acetate. The reaction mixture was filteredthrough a 0.45 micron filter cartridge that was rinsed with ethylacetate. The filtrate was concentrated to a brown oil, which was thendissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred for 40 min. Thereaction mixture was concentrated and purified via preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to afford thedesired product (1.70 mg, 23.1%). LCMS for C₃₂H₃₄N₅O₇S (M+H)⁺:m/z=632.2; Found: 632.2.

Example 16.N-(4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzyl)acetamide

Step 2.N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide

A solution of 4-dimethylaminopyridine (1.048 mg, 8.58 μmol) and(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine(0.020 g, 0.086 mmol) [Combi-Blocks, cat #PN-2443] in dichloromethane(0.572 mL) and triethylamine (0.018 mL, 0.129 mmol) was treated withacetic anhydride (0.024 mL, 0.257 mmol), and the mixture was stirred atroom temp over a weekend. Purification of the reaction mixture by flashcolumn chromatography using methanol in dichloromethane (0% to 20%)afforded the desired product (18 mg, 76.3%) as an oily white solid. LCMSfor C₁₅H₂₃BNO₃ (M+H)⁺: m/z=276.2; Found: 276.3.

Step 2.N-(4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzyl)acetamide

A solution of tert-butyl2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(6.0 mg, 8.16 μmol),N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)acetamide (6.73mg, 0.024 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.999 mg, 1.22 μmol) in 1,4-dioxane (0.181 mL),and potassium carbonate (1.0 M in water, 0.041 mL, 0.041 mmol) wasbubbled with nitrogen for 5 min. The sealed vial was heated at 80° C.for 6 h, then cooled to room temperature and held overnight. Ethylacetate was added to the reaction mixture, which was then filteredthrough a 0.45 micron filter cartridge. The solids were rinsed withethyl acetate and the filtrate was concentrated to a brown oil. The oilwas dissolved in dry THE (0.50 mL), sodium methoxide (25 wt % inmethanol, 0.028 mL, 0.12 mmol) was added, and the mixture was stirred atroom temp for 30 minutes. The mixture was then diluted with methanol,deionized water, and 1 N HCl (0.1 mL). The resulting solution waspurified via preparative LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.1% trifluoroacetic acid, atflow rate of 60 mL/min) to afford a crude material. The crude materialwas purified via preparative LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.1% ammonium hydroxide, at flowrate of 60 mL/min) to afford the desired product (2.3 mg, 42.9%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.42 (t, J=6.2Hz, 1H), 7.99 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.32 (s, 4H), 7.22 (d,J=8.1 Hz, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.96 (s, 2H), 3.45 (s, 2H), 3.26(s, 3H), 3.04 (t, J=12.4 Hz, 1H), 2.91 (s, 3H), 2.89 (s, 2H), 2.00-1.93(m, 4H), 1.90 (s, 3H), 1.66-1.53 (m, 2H), 1.11 (s, 9H). LCMS forC₃₆H₄₅N₆O₄S (M+H)⁺: m/z=657.3; Found: 657.3.

Examples 17-18

Examples 17-18 of Table 4 were prepared according to proceduresdescribed in Example 16.

TABLE 4

Ex. LCMS ¹H NMR No. Name R [M + H]⁺ Spectrum 17 4-(2-(tert-Butyl)-4-methyl-8-(4-((4- (methylsulfonyl)piperidin- 1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro- 1H-pyrrolo [3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N- methylbenzenesulfonamide, trifluoroacetic acid salt

679.2 — 18 9-(4-(4-Acetylpiperazin- 1-yl)phenyl)-2-(tert-butyl)-4-methyl-8-(4-((4- (methylsulfonyl)piperidin-1-yl)methyl)phenyl)- 1,2,4,7-tetrahydro-3H- pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one, trifluoroacetic acid salt

712.4 ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 9.45 (s, 1H), 8.02 (s,1H), 7.60 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 7.26 (d, J =8.4 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 4.27 (s, 2H), 4.02 (s, 2H), 3.26(s, 3H), 3.21 (t, J = 5.4 Hz, 2H), 3.15 (t, J = 5.2 Hz, 2H), 2.99 (s,3H), 2.25 (d, J = 13.8 Hz, 2H), 2.07 (s, 3H), 1.84 (q, J = 13.0 Hz, 2H),1.13 (s, 9H).

Example 19.2-(4-(4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)phenyl)-1H-pyrazol-1-yl)propanamideTrifluoroacetic Acid Salt

Step 1.4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole

A mixture of 4-(4-bromophenyl)-1H-pyrazole (0.150 g, 0.672 mmol) [MatrixScientific, cat #016087], bis(pinacolato)diboron (0.256 g, 1.009 mmol),and potassium acetate (0.198 g, 2.017 mmol) in 1,4-dioxane (4.48 mL) wasbubbled with nitrogen for 5 min.Dichlorobis(triphenylphosphine)-palladium(II) (0.071 g, 0.101 mmol) wasadded and the resulting mixture was bubbled with nitrogen for anadditional 5 min. The mixture was then heated in a sealed vial at 110°C. for 18 h. THE was added, and the reaction mixture was filtered. Thesolids were rinsed with additional THE and the filtrate was concentratedto a hazy yellow oil. Purification by flash column chromatography usingethyl acetate in hexanes (0% to 100%) afforded the desired product (136mg, 74.9%) as a gummy white solid. LCMS for C₁₅H₂₀BN₂O₂(M+H)⁺:m/z=271.2; Found: 271.1.

Step 2.2-(4-(4-(2-(tert-Butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)phenyl)-1H-pyrazol-1-yl)propanamideTrifluoroacetic Acid Salt

A mixture of 2-bromopropionamide (5.06 mg, 0.033 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(0.009 g, 0.033 mmol), and cesium carbonate (0.033 g, 0.100 mmol) in dryacetonitrile (0.133 mL) was heated in sealed vial at 75° C. for 17 h.The mixture was cooled to room temperature and concentrated. To theresidue was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.999 mg, 1.22 μmol), followed by a solution oftert-butyl2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(6.0 mg, 8.16 μmol) in 1,4-dioxane (0.181 mL) and potassium carbonate(1.0 M in water, 0.041 mL, 0.041 mmol). The mixture was bubbled withnitrogen for 5 min and heated in a sealed vial at 80° C. for 6 h. Ethylacetate was added and the reaction mixture was filtered through a 0.45micron filter cartridge. The solids were rinsed with additional ethylacetate and the filtrate was concentrated. The resulting residue wasdissolved in dry THF (0.50 mL), sodium methoxide (25 wt % in methanol,0.019 mL, 0.082 mmol) was added, and the mixture was stirred at roomtemp for 20 min. Methanol, deionized water, and 1 N HCl (˜0.1 mL) wereadded, and the resulting solution was purified via preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to afford theracemic desired product (0.9 mg, 13.2%) as a yellow solid. LCMS forC₃₉H₄₇N₈O₄S (M+H)⁺: m/z=723.3; Found: 723.2.

Example 20.4-(9-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

A mixture of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(Example 11, Step 11, 8.0 mg, 9.35 μmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (1.15 mg, 1.40 μmol), and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one(7.04 mg, 0.028 mmol) was stirred in 1,4-dioxane (0.21 mL) and potassiumcarbonate (1.0 M in water, 0.047 mL, 0.047 mmol). The mixture wasbubbled with nitrogen for 5 min and heated in a sealed vial at 80° C.for 6 h. The mixture was diluted with ethyl acetate and filtered througha 0.45 micron filter cartridge. The solids were rinsed with additionalethyl acetate and concentrated. The resulting residue was dissolved indichloromethane (0.50 mL), TFA (0.50 mL) was added, and the resultingmixture was stirred at room temp for 45 min, and then concentrated. Theresidue was dissolved in methanol and deionized water. The resultingsolution was purified via preparative LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.1% trifluoroacetic acid,at flow rate of 60 mL/min) to afford the desired product (6.2 mg, 81.8%)as a light tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 9.59(s, 1H), 8.18 (s, 1H), 7.95 (dd, J=8.4, 5.5 Hz, 2H), 7.88 (dd, J=8.3,4.6 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.39 (d,J=8.4 Hz, 1H), 5.94-5.87 (m, 1H), 5.19-5.12 (m, 2H), 4.38-4.33 (m, 2H),4.17-4.11 (m, 1H), 3.65-3.53 (m, 3H), 3.47-3.37 (m, 4H), 3.10-2.94 (m,5H), 2.32-2.12 (m, 4H), 2.04 (d, J=10.6 Hz, 3H), 1.95-1.81 (m, 2H). LCMSfor C₃₇H₄₁N₆O₆S (M+H)⁺: m/z=697.3; Found: 697.3.

Examples 21-23

Examples 21-23 of Table 5 were prepared according to proceduresdescribed in to Example 20.

TABLE 5

Ex. LCMS ¹H NMR No. Name R [M + H]⁺ Spectrum 21 4-(9-(4-(1-Aminocyclopropyl) phenyl)-4-methyl-8-(4-((4- (methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3- oxo-1,3,4,7-tetrahydro- 2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d] pyrimidin-2-yl)benzoic acid trifluoroacetic acid salt(1:2)

705.2 — 22 4-(4-Methyl-9-(1- methyl-1H-pyrrol-3-yl)- 8-(4-((4-(methylsulfonyl)piperidin- 1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro- 2H-

653.2 ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.49 (s, 1H), 8.14 (s,1H), 7.90 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 7.9 Hz, 2H), 7.46 (d, J =8.1 Hz, 2H), 7.25 pyrrolo[3′,2′:5,6]pyrido (d, J = 8.6 Hz, 2H),[3,4-d]pyrimidin-2- 6.87-6.84 (m, 1H), yl)benzoic acid 6.75-6.72 (m,1H), trifluoroacetic acid salt 6.04-6.01 (m, 1H), 4.69 (s, 2H), 4.33-4.26 (m, 1H), 3.66 (s, 3H), 3.58-3.50 (m, 2H), 2.99 (m, 4H), 3.41 (s,3H), 2.25 (d, J = 13.5 Hz, 2H), 1.92-1.79 (m, 2H). 234-(9-Cyclopropyl-4- methyl-8-(4-((4- (methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3- oxo-1,3,4,7-tetrahydro-

614.2 ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 9.63 (s, 1H), 8.13 (s,1H), 7.98 (d, J = 8.3 Hz, 2H), 7.89 (d, 2H- J = 7.9 Hz, 2H), 7.62 (d,pyrrolo[3′,2′:5,6]pyrido J = 7.9 Hz, 2H), 7.55 [3,4-d]pyrimidin-2- (d, J= 8.4 Hz, 2H), yl)benzoic acid, 5.53 (s, 2H), 4.42- trifluoroacetic acidsalt 4.38 (m, 2H), 3.12- 2.96 (m, 5H), 2.33- 2.26 (m, 2H), 2.21- 2.12(m, 2H), 1.96- 1.82 (m, 2H), 1.24 (s, 1H), 0.92 (d, J = 7.5 Hz, 2H),0.22 (d, J = 5.2 Hz, 2H).

Example 24.4-(9-Cyano-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

A solution of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate(Example 11, Step 11, 8.0 mg, 9.35 μmol), zinc cyanide (1.65 mg, 0.014mmol), and tetrakis(triphenylphosphine)palladium(0) (1.08 mg, 0.935μmol) in DMF (0.623 mL) was bubbled with nitrogen for 5 min. The mixturewas capped and heated in the microwave at 150° C. for 1 h. Acetonitrilewas added, and the reaction mixture was filtered through 0.45 micronfilter cartridge. The solids were rinsed with ethyl acetate and thefiltrate was concentrated to a yellow oil. The resulting oil was placedon high vacuum for 1 h, then dissolved in a mixture of dichloromethane(0.50 mL) and TFA (0.50 mL), then stirred at room temp for 1 h. Thereaction mixture was concentrated and the resulting residue wasdissolved in acetonitrile and water. The solution was purified viapreparative LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min) to afford the desired product (2.8 mg, 42.0%) as a yellow solid.LCMS for C₃₁H₃₁NA₆O₅S (M+H)⁺: m/z=599.2; Found: 599.1.

Example 25.4-(9-Iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

Step 1.4-(4-Methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid Trifluoroacetic Acid Salt

A solution of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(Example 11, Step 8, 0.17 g, 0.221 mmol) in THE (4.0 mL), methanol (4.00mL), and 1.78 M KOH in water (4.0 mL, 7.12 mmol) was stirred overnight,affording a precipitate. Dichloromethane and deionized water were addedto the reaction mixture. The organic layer was collected to isolatetert-Butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate(Example 11, Step 9). The aqueous layer was treated with TFA (0.60 mL,7.79 mmol), which afforded solids. The solids were dissolved by DMF (10mL) addition, and the resulting solution was purified via preparativeLCMS (XBridge C18 Column, eluting with a gradient of acetonitrile inwater with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) toafford the desired product (20 mg, 11.3%). LCMS for C₃₀H₃₂N₅O₅S (M+H)⁺:m/z=574.2; Found: 573.9.

Step 2.4-(9-Iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid, Trifluoroacetic Acid Salt

To a solution of4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid trifluoroacetic acid salt (10 mg, 0.0146 mmol) in DMF (1.0 mL) wasadded NIS (3.20 mg, 0.0142 mmol). The reaction mixture was diluted withmethanol and purified via preparative LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.1% trifluoroacetic acid,at flow rate of 60 mL/min) to afford the desired product (3.0 mg,25.3%). LCMS for C₃₀H₃₁IN₅O₅S (M+H)⁺: m/z=700.1; Found: 700.1.

Example 26.4-(8-Cyclopropyl-9-(4-methoxyphenyl)-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid

Step 1. tert-Butyl4-(8-cyclopropyl-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

The title compound was prepared according to the procedures described inExample 11, Step 12, using tert-butyl4-(8-bromo-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoateand potassium cyclopropyltrifluoroborate in place of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylateand (4-methoxyphenyl)boronic acid as the starting materials. LCMS forC₃₀H₃₁N₄O₅S (M+H)⁺: m/z=559.2; Found: 559.2.

Step 2. tert-Butyl4-(8-cyclopropyl-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

The title compound was prepared according to the procedures described inExample 11, Step 9, using tert-butyl4-(8-cyclopropyl-4-methyl-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoatein place of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoateas the starting material. LCMS for C₂₄H₂₇N₄O₃ (M+H)⁺: m/z=419.2; Found:419.2.

Step 3. tert-Butyl4-(8-cyclopropyl-9-iodo-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoate

The title compound was prepared according to the procedures described inExample 11, Step 10, using tert-butyl4-(8-cyclopropyl-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoatein place of tert-butyl4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoateas the starting material. LCMS for C₂₄H₂₆IN₄O₃(M+H)⁺: m/z=545.1; Found:545.1.

Step 4. tert-Butyl2-(4-(tert-butoxycarbonyl)phenyl)-8-cyclopropyl-9-iodo-4-methyl-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylate

The title compound was prepared according to the procedures described inExample 11, Step 11, using tert-butyl4-(8-cyclopropyl-9-iodo-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoatein place of tert-butyl4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoateas the starting material. LCMS for C₂₉H₃₄1N₄O₅(M+H)⁺: m/z=645.2; Found:645.1.

Step 5.4-(8-Cyclopropyl-9-(4-methoxyphenyl)-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid

The title compound was prepared according to the procedures described inExample 20, using tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-8-cyclopropyl-9-iodo-4-methyl-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylateand (4-methoxyphenyl)boronic acid in place of tert-butyl2-(4-(tert-butoxycarbonyl)phenyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidine-7-carboxylateand1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-oneas the starting materials. LCMS for C₂₇H₂₅N₄O₄ (M+H)⁺: m/z=469.2; Found:469.1.

Example A. JAK2 LanthaScreen JH1 Binding Assay

JAK2 JH1 binding assay utilizes catalytic domain (JH1, amino acids826-1132) of human JAK2 expressed as N-terminal FLAG-tagged,biotinylated protein in a baculovirus expression system (CarnaBiosciences, Product #08-445-20N). The assay was conducted in black384-well polystyrene plates in a final reaction volume of 20 μL. JAK2JH1 (1.5 nM) was incubated with compounds (100 nL serially diluted inDMSO) in the presence of 50 nM Fluorescent JAK2-JH1 Tracer and 0.5 nMStreptavidin-Tb cryptate (Cisbio Part #610SATLB) in assay buffer (50 mMTris, pH=7.5, 10 mM MgCl₂, 0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5%Glycerol and 5 mM DTT). Non-specific binding was accessed in thepresence of 2 mM ATP. After incubation for 2 hours at 25° C.,LanthaScreen signals were read on a PHERAstar FS plate reader (BMGLABTECH). Data was analyzed with IDBS XLfit and GraphPad Prism 5.0software using a four parameter dose response curve to determine IC50for each compound.

Example B. JAK2 LanthaScreen JH2-WT Binding Assay

JAK2 JH2-WT binding assay utilizes pseudo-kinase domain (JH2,amino-acids 536-812 with 3 surface mutations W659A, W777A, F794H) ofhuman Wild Type JAK2 expressed as C-terminal His-Avi-tagged,biotinylated protein in a baculovirus expression system (BPS Bioscience,Catalog #79463). The assay was conducted in black 384-well polystyreneplates in a final reaction volume of 20 μL. JAK2 JH2-WT (0.145 nM) wasincubated with compounds (100 nL serially diluted in DMSO) in thepresence of 50 nM Fluorescent JAK2-JH2 Tracer (MedChem Express Catalog#HY-102055) and 0.25 nM Streptavidin-Tb cryptate (Cisbio Part #610SATLB)in assay buffer (50 mM Tris, pH=7.5, 10 mM MgCl₂, 0.01% Brij-35, 0.1%BSA, 1 mM EGTA, 5% Glycerol and 5 mM DTT). Non-specific binding wasaccessed in the presence of 2 mM ATP. After incubation for 1 hour at 25°C., LanthaScreen signals were read on a PHERAstar FS plate reader (BMGLABTECH). Data was analyzed with IDBS XLfit and GraphPad Prism 5.0software using a four parameter dose response curve to determine IC50for each compound.

Example C. JAK2 LanthaScreen JH2-V617F Binding Assay

JAK2 JH2-V617F binding assay utilizes pseudo-kinase domain (JH2,amino-acids 536-812 with 3 surface mutations W659A, W777A, F794H) ofhuman V617F mutant JAK2 expressed as C-terminal His-Avi-tagged,biotinylated protein in a baculovirus expression system (BPS Bioscience,Catalog #79498). The assay was conducted in black 384-well polystyreneplates in a final reaction volume of 20 μL. JAK2 JH2-V617F (0.26 nM) wasincubated with compounds (100 nL serially diluted in DMSO) in thepresence of 50 nM Fluorescent JAK2-JH2 Tracer (MedChem Express Catalog#HY-102055) and 0.25 nM Streptavidin-Tb cryptate (Cisbio Part #610SATLB)in assay buffer (50 mM Tris, pH=7.5, 10 mM MgCl₂, 0.01% Brij-35, 0.1%BSA, 1 mM EGTA, 5% Glycerol and 5 mM DTT). Non-specific binding wasaccessed in the presence of 2 mM ATP. After incubation for 1 hour at 25°C., LanthaScreen signals were read on a PHERAstar FS plate reader (BMGLABTECH). Data was analyzed with IDBS XLfit and GraphPad Prism 5.0software using a four parameter dose response curve to determine IC50for each compound.

Example D. JAK2 HTRF Enzyme Activity Assay

JAK2 enzyme activity assays utilize catalytic domain (JH1, amino acids808-1132) of human JAK2 expressed as N-terminal His-tagged protein in abaculovirus expression system (BPS Bioscience, Catalog #40450). Theassays was conducted in black 384-well polystyrene plates in a finalreaction volume of 20 μL. JAK2 (0.015 nM) was incubated with compounds(100 nL serially diluted in DMSO) in the presence of ATP (30 μM or 1 mM)and 500 nM Biotin-labeled EQEDEPEGDYFEWLE (SEQ ID NO.: 1) peptide(BioSource International, custom synthesis) in assay buffer (50 mM Tris,pH=7.5, 10 mM MgCl₂, 0.01% Brij-35, 0.1% BSA, 1 mM EGTA, 5% Glycerol and5 mM DTT) for 60 minutes at 25° C. The reactions were stopped by theaddition of 10 μL of detection buffer (50 mM Tris, pH 7.8, 0.5 mg/mLBSA, 150 mM NaCl), supplemented with EDTA, LANCE Eu-W1024anti-phosphotyrosine (PY20), (PerkinElmer, Catalog #AD0067) andStreptavidin SureLight APC (PerkinElmer Catalog #CR130-100), for a finalconcentration of 15 mM, 1.5 nM and 75 nM, respectively. HTRF signalswere read after 30 minutes incubation at room temperature on a PHERAstarFS plate reader (BMG LABTECH). Data was analyzed with IDBS XLfit andGraphPad Prism 5.0 software using a four parameter dose response curveto determine IC50 for each compound.

The compounds of the disclosure were tested in one or more of the assaysdescribed in Examples A-D, and the resulting data are shown in Table A.

TABLE A JH2 BIND Ex. JH1 BIND JH2 BIND WT V617F ENZYME No. IC₅₀ (nM)IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 + ++ +++ + 2 + ++ +++ + 3 ++++ + + ++++4 ++ ++ ++ ++ 5 + ++ +++ + 6 ++ ++++ +++++ ++ 7 + +++ ++++ + 8 ++ ++ +++++ 9 ++ ++ ++ ++ 10 ++++ + ++ ++++ 11 +++++ + + +++++ 12 ++++ + + ++++13 ++++ + + ++++ 14 + + + + 15 +++++ ++ ++ +++++ 16 + + + + 17 + + + +18 + + + + 19 + + + + 20 +++++ + + +++++ 21 ++++ + + +++++ 22 ++++ + +++++ 23 +++++ + + +++++ 24 +++++ ++ ++ +++++ 25 +++ + + ++++ 26 +++++ ++++ +++++ + refers to IC₅₀ of ≤100 nM ++ refers to IC₅₀ of >100 nM to≤500 nM +++ refers to IC₅₀ of >500 nM to ≤1000 nM ++++ refers to IC₅₀of >1000 nM to ≤2500 nM +++++ refers to IC₅₀ of >2500 nM

Example E. Cell Culture and STAT5 (Tyr694) Phosphorylation Cell BasedAssay

Ba/F3 cells expressing human JAK2 V617F/EPOR (mouse JAK2 WT knocked outby CRISPR) are cultured in RPMI media with 10% FBS, 1l g/mL Puromycin, 1mg/mL Geneticin (Thermo Fisher). Ba/F3 cells expressing human JAK2WT/EPOR are cultured in RPMI media with 10% FBS, 1 μg/mL Puromycin, 1mg/mL Geneticin and 2 ng/mL EPO. 24 hours before the assay, the culturemedium for JAK2 V617F/EPOR Ba/F3 cells are changed to RPMI with 10% FBSwithout antibiotic (assay medium 1). Culture medium for Ba/F3 cellsexpressing human JAK2 WT/EPOR are changed to RPMI with 10% FBS and 2ng/mL EPO (R&D systems) without antibiotic (assay medium 2). 50 nL/welltest compounds in DMSO are transferred to the 384 white low volume cellculture plate (Greiner Bio-one) by ECHO liquid handler (Labcyte). Thecells are centrifuged, resuspended in the corresponding fresh assaymedium and dispensed at L/well (6×10⁶ cells/mL) with 0.5% DMSO in thefinal assay. After the treated cells are incubated at 37° C., 5% CO₂ for2 hours, 4 μL/well supplemented lysis buffer (100× blocking bufferdiluted 25 fold in 4× lysis buffer, Perkin-Elmer) are added andincubated at room temperature for 60 min with gentle shaking on orbitalshaker at 600 rpm. Phospho-STAT5 Cryptate antibody and Phospho-STAT5 d2antibody (1:1 vol/vol, Perkin-Elmer) are premixed and diluted 20 foldwithin the detection buffer. 4 μL of the premixed antibody solution areadded to each well followed with 16 hours incubation at roomtemperature. The product activity is determined by measuring thefluorescence at 620 nm and 665 nm on Pherastar microplate reader (BMGLabtech). A ratio is calculated (665/620 nm) for each well. Wells withDMSO serve as the positive controls and wells containing highconcentration of control compound are used as negative controls. IC₅₀determination is performed by fitting the curve of percent controlactivity versus the log of the compound concentration using the GenedataScreener software.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R¹ are each optionallysubstituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R^(M)substituents; R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R² are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2A) substituents; each R^(2A) is independently selected fromhalo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a21), SR^(a21), NHOR^(a21),C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21),NR^(c21)C(O)NR^(c21)R^(d21), C(═NR^(e21))R^(b21),C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))R^(b21), NR^(c21)S(O)R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), and OS(O)₂R^(b21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2B) substituents; each R^(a21), R^(c21), and R^(d21) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(c21) andR^(d21) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2B) substituents; or, any R^(c21) and R^(d21)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(2B) substituents; each R^(b21) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b21) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2B) substituents; each R^(e21) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(2B) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22),C(O)NR^(c22)R^(d22), C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)R^(b22), NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), and OS(O)₂R^(b22), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2C) substituents; each R^(a22), R^(c22), and R^(d22) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a22), R^(c22) andR^(d22) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(2C) substituents; or, any R^(c22) and R^(d22)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(2C) substituents; each R^(b22) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b22) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(2C) substituents; each R^(e22) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(2C) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a23), SR^(a23), NHOR^(a23), C(O)R^(b23),C(O)NR^(c23)R^(d23), C(O)NR^(c23)(OR^(a23)), C(O)OR^(a23), OC(O)R^(b23),OC(O)NR^(c23)R^(d23), NR^(c23)R^(d23), NR^(c23)NR^(c23)R^(d23),NR^(c23)C(O)R^(b23), NR^(c23)C(O)OR^(a23), NR^(c23)C(O)NR^(c23)R^(d23),C(═NR^(e23))R^(b23), C(═NR^(e23))NR^(c23)R^(d23),NR^(c23)C(═NR^(e23))NR^(c23)R^(d23), NR^(c23)C(═NR^(e23))R^(b23),NR^(c23)S(O)R^(b23), NR^(c23)S(O)NR^(c23)R^(d23), NR^(c23)S(O)₂R^(b23),NR^(c23)S(O)(═NR^(e23))R^(b23), NR^(c23)S(O)₂NR^(c23)R^(d23),S(O)R^(b23), S(O)NR^(c23)R^(d23), S(O)₂R^(b23), S(O)₂NR^(c23)R^(d23),OS(O)(═NR^(e23))R^(b23), and OS(O)₂R^(b23), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a23), R^(c23), and R^(d23) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a23), R^(c23) and R^(d23) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents; or, any R^(c23)and R^(d23) attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl or4-7 membered heterocycloalkyl group is optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(b23) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b23) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(e23) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; R³ and R^(3′) are each independentlyselected from H, D, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a3), SR^(a3), NHOR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)NR^(c3)(OR^(a3)), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))R^(b3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)NR^(c3)R^(d3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)(═NR^(e3))R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3),OS(O)(═NR^(e3))R^(b3), and OS(O)₂R^(b3), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R³ are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3A) substituents; or, R³ and R^(3′) attached to the same Catom, together with the C atom to which they are attached, form a 3-10membered cycloalkyl or a 4-10 membered heterocycloalkyl group, whereinthe 3-10 membered cycloalkyl or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3A) substituents; each R^(a3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a3), R^(c3) andR^(d3) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3A) substituents; or, any R^(c3) and R^(d3)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(3A) substituents; each R^(b3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b3) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3A) substituents; each R^(e3) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(3A) isindependently selected from D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a31),SR^(a31), NHOR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),C(O)NR^(c31)(OR^(a31)), C(O)OR^(a31), OC(O)R^(b31),OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c31)NR^(c31)R^(d31),NR^(c31)C(O)R^(b31), NR^(c31)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31),C(═NR^(e31))R^(b31), C(═NR^(e31))NR^(c31)R^(d31),NR^(c31)C(═NR^(e31))NR^(c31)R^(d31), NR^(c31)C(═NR^(e31))R^(b31),NR^(c31)S(O)R^(b31), NR^(c31)S(O)NR^(c31)R^(d31), NR^(c31)S(O)₂R^(b31),NR^(c31)S(O)(═NR^(e31))R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31),S(O)R^(b31), S(O)NR^(c31)R^(d31), S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31),OS(O)(═NR^(e31))R^(b31), and OS(O)₂R^(b31), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3B) substituents; each R^(a31), R^(c31), and R^(d31) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a31), R^(c31) andR^(d31) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3B) substituents; or, any R^(c31) and R^(d31)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(3B) substituents; each R^(b31) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b31) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3B) substituents; each R^(e31) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(3B) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a32), SR^(a32), NHOR^(a32), C(O)R^(b32),C(O)NR^(c32)R^(d32), C(O)NR^(c32)(OR^(a32)), C(O)OR^(a32), OC(O)R^(b32),OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)NR^(c32)R^(d32),NR^(c32)C(O)R^(b32), NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32),C(═NR^(e32))R^(b32), C(═NR^(e32))NR^(c32)R^(d32),NR^(c32)C(═NR^(e32))NR^(c32)R^(d32), NR^(c32)C(═NR^(e32))R^(b32),NR^(c32)S(O)R^(b32), NR^(c32)S(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),NR^(c32)S(O)(═NR^(e32))R^(b32), NR^(c32)S(O)₂NR^(c32)R^(d32),S(O)R^(b32), S(O)NR^(c32)R^(d32), S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32),OS(O)(═NR^(e32))R^(b32), and OS(O)₂R^(b32), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(3B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3C) substituents; each R^(a32), R^(c32), and R^(d32) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a32), R^(c32) andR^(d32) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(3C) substituents; or, any R^(c32) and R^(d32)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(3C) substituents; each R^(b32) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b32) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(3C) substituents; each R^(e32) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(3C) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a33), SR^(a33), NHOR^(a33), C(O)R^(b33),C(O)NR^(c33)R^(d33), C(O)NR^(c33)(OR^(a33)), C(O)OR^(a33), OC(O)R^(b33),OC(O)NR^(c33)R^(d33), NR^(c33)R^(d33), NR^(c33)NR^(c33)R^(d33),NR^(c33)C(O)R^(b33), NR^(c33)C(O)OR^(a33), NR^(c33)C(O)NR^(c33)R^(d33),C(═NR^(e33))R^(b33), C(═NR^(e33))NR^(c33)R^(d33),NR^(c33)C(═NR^(e33))NR^(c33)R^(d33), NR^(c33)C(═NR^(e33))R^(b33),NR^(c33)S(O)R^(b33), NR^(c33)S(O)NR^(c33)R^(d33), NR^(c33)S(O)₂R^(b33),NR^(c33)S(O)(═NR^(e33))R^(b33), NR^(c33)S(O)₂NR^(c33)R^(d33),S(O)R^(b33), S(O)NR^(c33)R^(d33), S(O)₂R^(b33), S(O)₂NR^(c33)R^(d33),OS(O)(═NR^(e33))R^(b33), and OS(O)₂R^(b33), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(3C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a33), R^(c33), and R^(d33) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a33), R^(c33) and R^(d33) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents; or, any R^(c33)and R^(d33) attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl or4-7 membered heterocycloalkyl group is optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(b33) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b33) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(e33) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; R⁴ is selected from H, D, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a4), SR^(a4), NHOR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)NR^(c4)(OR^(a4)), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))R^(b4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)NR^(c4)R^(d4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)(═NR^(e4))R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂NR^(c4)R^(d4), OS(O)(═NR^(e4))R^(b4), and OS(O)₂R^(b4), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁴ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(4A) substituents; each R^(a4), R^(c4),and R^(d4) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a4),R^(c4) and R^(d4) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(4A) substituents; or, any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(4A) substituents; each R^(b4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b4) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4A) substituents; each R^(e4) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(4A) isindependently selected from D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a41),SR^(a41), NHOR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),C(O)NR^(c41)(OR^(a41)), C(O)OR^(a41), OC(O)R^(b41),OC(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), NR^(c41)C(O)OR^(a41), NR^(c41)C(O)NR^(c41)R^(d41),C(═NR^(e41))R^(b41), C(═NR^(e41))NR^(c41)R^(d41),NR^(c41)C(═NR^(e41))NR^(c41)R^(d41), NR^(c41)C(═NR^(e41))R^(b41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)NR^(c41)R^(d41), NR^(c41)S(O)₂R^(b41),NR^(c41)S(O)(═NR^(e41))R^(b41), NR^(c41)S(O)₂NR^(c41)R^(d41),S(O)R^(b41), S(O)NR^(c41)R^(d41), S(O)₂R^(b41), S(O)₂NR^(c41)R^(d41),OS(O)(═NR^(e41))R^(b41), and OS(O)₂R^(b41), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4B) substituents; each R^(a41), R^(c41), and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4B) substituents; or, any R^(c41) and R^(d41)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(4B) substituents; each R^(b41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b41) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4B) substituents; each R^(e41) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(4B) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a42), SR^(a42), NHOR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)NR^(c42)(OR^(a42)), C(O)OR^(a42), OC(O)R^(b42),OC(O)NR^(c42)R^(d42), NR^(c42)R^(d42), NR^(c42)NR^(c42)R^(d42)NR^(c42)C(O)R^(b42), NR^(c42)C(O)OR^(a42), NR^(c42)C(O)NR^(c42)R^(d42),C(═NR^(e42))R^(b42), C(═NR^(e42))NR^(c42)R^(d42),NR^(c42)C(═NR^(e42))NR^(c42)R^(d42), NR^(c42)C(═NR^(e42))R^(b42),NR^(c42)S(O)R^(b42), NR^(c42)S(O)NR^(c42)R^(d42), NR^(c42)S(O)₂R^(b42),NR^(c42)S(O)(═NR^(e42))R^(b42), NR^(c42)S(O)₂NR^(c42)R^(d42),S(O)R^(b42), S(O)NR^(c42)R^(d42), S(O)₂R^(b42), S(O)₂NR^(c42)R^(d42),OS(O)(═NR^(e42))R^(b42), and OS(O)₂R^(b42), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(4B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4C) substituents; each R^(a42), R^(c42), and R^(d42) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a42), R^(c42) andR^(d42) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(4C) substituents; or, any R^(c42) and R^(d42)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(4C) substituents; each R^(b42) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b42) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(4C) substituents; each R^(e42) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(4C) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a43), SR^(a43), NHOR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), C(O)NR^(c43)(OR^(a43)), C(O)OR^(a43), OC(O)R^(b43),OC(O)NR^(c43)R^(d43), NR^(c43)R^(d43), NR^(c43)NR^(c43)R^(d43),NR^(c43)C(O)R^(b43), NR^(c43)C(O)OR^(a43), NR^(c43)C(O)NR^(c43)R^(d43),C(═NR^(e43))R^(b43), C(═NR^(e43))NR^(c43)R^(d43),NR^(c43)C(═NR^(e43))NR^(c43)R^(d43), NR^(c43)C(═NR^(e43))R^(b43),NR^(c43)S(O)R^(b43), NR^(c43)S(O)NR^(c43)R^(d43), NR^(c43)S(O)₂R^(b43),NR^(c43)S(O)(═NR^(e43))R^(b43), NR^(c43)S(O)₂NR^(c43)R^(d43),S(O)R^(b43), S(O)NR^(c43)R^(d43), S(O)₂R^(b43), S(O)₂NR^(c43)R^(d43),OS(O)(═NR^(e43))R^(b43), and OS(O)₂R^(b43), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(4C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a43), R^(c43), and R^(d43) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a43), R^(c43) and R^(d43) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents; or, any R^(c43)and R^(d43) attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl or4-7 membered heterocycloalkyl group is optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(b43) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b43) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(e43) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; R⁵ is selected from H, D, halo, C₂₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a5), SR^(a5), NHOR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)NR^(c5)(OR^(a5)), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))R^(b5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)NR^(c5)R^(d5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)(═NR^(e5))R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),S(O)₂NR^(c5)R^(d5), OS(O)(═NR^(e5))R^(b5), and OS(O)₂R^(b5), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁵ are each optionally substituted with 1, 2, 3, 4, 5, 6, 7,or 8 independently selected R^(5A) substituents; each R^(a5), R^(c5),and R^(d5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a5),R^(c5) and R^(d5) are each optionally substituted with 1, 2, 3, 4, 5, 6,7, or 8 independently selected R^(5A) substituents; or, any R^(c5) andR^(d5) attached to the same N atom, together with the N atom to whichthey are attached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(5A) substituents; each R^(b5) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b5) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5A) substituents; each R^(e5) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-; each R^(5A) isindependently selected from D, halo, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a51),SR^(a51), NHOR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51),C(O)NR^(c51)(OR^(a51)), C(O)OR^(a51), OC(O)R^(b51),OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51), NR^(c51)NR^(c51)R^(d51),NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR^(c51)C(O)NR^(c51)R^(d51),C(═NR^(e51))R^(b51), C(═NR^(e51))NR^(c51)R^(d51),NR^(c51)C(═NR^(e51))NR^(c51)R^(d51), NR^(c51)C(═NR^(e51))R^(b51),NR^(c51)S(O)R^(b51), NR^(c51)S(O)NR^(c51)R^(d51), NR^(c51)S(O)₂R^(b51),NR^(c51)S(O)(═NR^(e51))R^(b51), NR^(c51)S(O)₂NR^(c51)R^(d51),S(O)R^(b51), S(O)NR^(c51)R^(d51), S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51),OS(O)(═NR^(e51))R^(b51), and OS(O)₂R^(b51), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5B) substituents; each R^(a51), R^(c51), and R^(d51) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a51), R^(c51) andR^(d51) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5B) substituents; or, any R^(c51) and R^(d51)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(5B) substituents; each R^(b51) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b51) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5B) substituents; each R^(e51) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(5B) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a52), SR^(a52), NHOR^(a52), C(O)R^(b52),C(O)NR^(c52)R^(d52), C(O)NR^(c52)(OR^(a52)), C(O)OR^(a52), OC(O)R^(b52),OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52), NR^(c52)NR^(c52)R^(d52),NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52), NR^(c52)C(O)NR^(c52)R^(d52),C(═NR^(e52))R^(b52), C(═NR^(e52))NR^(c52)R^(d52),NR^(c52)C(═NR^(e52))NR^(c52)R^(d52), NR^(c52)C(═NR^(e52))R^(b52),NR^(c52)S(O)R^(b52), NR^(c52)S(O)NR^(c52)R^(d52), NR^(c52)S(O)₂R^(b52),NR^(c52)S(O)(═NR^(e52))R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52),S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52),OS(O)(═NR^(e52))R^(b52), and OS(O)₂R^(b52), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5B) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5C) substituents; each R^(a52), R^(c52), and R^(d52) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a52), R^(c52) andR^(d52) are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8independently selected R^(5C) substituents; or, any R^(c52) and R^(d52)attached to the same N atom, together with the N atom to which they areattached, form a 5-10 membered heteroaryl or a 4-10 memberedheterocycloalkyl group, wherein the 5-10 membered heteroaryl or 4-10membered heterocycloalkyl group is optionally substituted with 1, 2, 3,or 4 independently selected R^(5C) substituents; each R^(b52) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(b52) are eachoptionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independentlyselected R^(5C) substituents; each R^(e52) is independently selectedfrom H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-; each R^(5C) is independently selected from D, halo, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a53), SR^(a53), NHOR^(a53), C(O)R^(b53),C(O)NR^(c53)R^(d53), C(O)NR^(c53)(OR^(a53)), C(O)OR^(a53), OC(O)R^(b53),OC(O)NR^(c53)R^(d53), NR^(c53)R^(d53), NR^(c53)NR^(c53)R^(d53),NR^(c53)C(O)R^(b53), NR^(c53)C(O)OR^(a53), NR^(c53)C(O)NR^(c53)R^(d53),C(═NR^(e53))R^(b53), C(═NR^(e53))NR^(c53)R^(d53),NR^(c53)C(═NR^(e53))NR^(c53)R^(d53), NR^(c53)C(═NR^(e53))R^(b53),NR^(c53)S(O)R^(b53), NR^(c53)S(O)NR^(c53)R^(d53), NR^(c53)S(O)₂R^(b53),NR^(c53)S(O)(═NR^(e53))R^(b53), NR^(c53)S(O)₂NR^(c53)R^(d53),S(O)R^(b53), S(O)NR^(c53)R^(d53), S(O)₂R^(b53), S(O)₂NR^(c53)R^(d53),OS(O)(═NR^(e53))R^(b53), and OS(O)₂R^(b53), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl,4-7 membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5C) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(a53), R^(c53), and R^(d53) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(a53), R^(c53) and R^(d53) are each optionally substituted with 1,2, 3, or 4 independently selected R^(M) substituents; or, any R^(c53)and R^(d53) attached to the same N atom, together with the N atom towhich they are attached, form a 5-6 membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5-6 membered heteroaryl or4-7 membered heterocycloalkyl group is optionally substituted with 1, 2,3, or 4 independently selected R^(M) substituents; each R^(b53) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(b53) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(M) substituents; eachR^(e53) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, C₃₋₇ cycloalkyl-C₁₋₆ alkyl-, (5-6membered heteroaryl)-C₁₋₆ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₆ alkyl-; and each R^(M) is independently selectedfrom H, D, OH, halo, oxo, CN, C(O)OH, NH₂, NO₂, SF₅, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H and C₁₋₆ alkyl.
 4. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom H and methyl.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is selected from H, C₁₋₆ alkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, and (5-10 membered heteroaryl)-C₁₋₆ alkyl-, whereinthe C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, and (5-10 memberedheteroaryl)-C₁₋₆ alkyl- of R² are each optionally substituted with 1, 2,3, or 4 independently selected R^(2A) substituents.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R² isselected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents.
 7. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R² is selectedfrom H, methyl, ethyl, isopropyl, tert-butyl, phenyl, cyclohexyl,piperidinyl, phenyl, pyridinylmethyl, phenylmethyl, and phenylethyl,wherein the methyl, ethyl, isopropyl, tert-butyl, phenyl, cyclohexyl,piperidinyl, phenyl, pyridinylmethyl, phenylmethyl, and phenylethyl ofR² are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(2A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b21),C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21),S(O)₂R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(2A) is independently selectedfrom halo, C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)NR^(c21)R^(a21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), whereinthe C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(a21), R^(b21), R^(c21), and R^(d21)are each independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents.
 11. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(a21), R^(b21), R^(c21), and R^(d21)are each independently selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21),R^(c21), and R^(d21) are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents.
 12. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R^(a21), R^(b21),R^(c21), and R^(d21) are each independently selected from H, methyl,ethyl, phenyl, pyridinyl, cyclopropyl, cyclohexyl,dihydroisobenzofuranyl, tetrahydrofuranyl, tetrahydropyranyl,phenylmethyl, cyclohexylmethyl, tetrahydropyranylmethyl,cyclopropylmethyl, and pyridinylmethyl of R^(a21), R^(b21), R^(c21), andR^(d21) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(2B) isindependently selected from halo, C₁₋₆ alkyl, CN, OR^(a22),C(O)OR^(a22), NR^(c22)R^(d22), wherein the C₁₋₆ alkyl is optionallysubstituted with 1 or 2 R^(2C) substituents independently selected fromOH and CN; and each R^(a22), R^(c22), and R^(d22) is independentlyselected from H and C₁₋₆ alkyl.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(2B) isindependently selected from methyl, hydroxy, methoxy, dimethylamino, CN,and C(O)OH.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is selected from H, methyl, ethyl,isopropyl, tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl,pyridinylmethyl, phenylmethyl, and phenylethyl, wherein the methyl,ethyl, isopropyl, tert-butyl, phenyl, cyclohexyl, piperidinyl, phenyl,pyridinylmethyl, phenylmethyl, and phenylethyl of R² are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; and each R^(2A) is independently selected from fluoro,chloro, bromo, methyl, ethyl, piperazinyl, morpholinyl, piperidinyl,morpholinylmethyl, dimethylamino, C(O)OH, C(O)NHCH₃, C(O)NHOCH₃,C(O)NHCH₂CH₂OH, C(O)NHCH₂CH₂OCH₃, C(O)N(CH₃)CH₂CH₂OH,C(O)N(CH₃)CH₂CH₂OCH₃, C(O)NHCH₂C(O)NHNHCH₂-phenyl, C(O)NH-cyclopropyl,C(O)NH-cyclohexyl, C(O)NH-phenyl, C(O)NH-pyridinyl,C(O)N(CH₃)-pyridinyl, C(O)NH-dihydroisobenzofuranyl,C(O)NH-tetrahydrofuranyl, C(O)NH-tetrahydropyranyl,C(O)N(CH₃)-tetrahydropyranyl, C(O)NH-(cyclopropylmethyl),C(O)NH-(cyclohexylmethyl), C(O)NH-(phenylmethyl),C(O)NH-(tetrahydropyranylmethyl), C(O)NH-(pyridinylmethyl),NHC(O)-tetrahydropyranyl, NHC(O)CH₂CN, NHC(O)CH₂CH₃, NHCH₂C(O)OH,NHCH₂CH₂OCH₃, and S(O)₂NH₂, wherein the methyl, ethyl, piperazinyl,morpholinyl, piperidinyl, morpholinylmethyl, C(O)NH-cyclopropyl,C(O)NH-cyclohexyl, C(O)NH-phenyl, C(O)NH-pyridinyl,C(O)N(CH₃)-pyridinyl, C(O)NH-dihydroisobenzofuranyl,C(O)NH-tetrahydrofuranyl, C(O)NH-tetrahydropyranyl,C(O)N(CH₃)-tetrahydropyranyl, C(O)NH-(cyclopropylmethyl),C(O)NH-(cyclohexylmethyl), C(O)NH-(phenylmethyl),C(O)NH-(tetrahydropyranylmethyl), C(O)NH-(pyridinylmethyl), andNHC(O)-tetrahydropyranyl, are each optionally substituted with 1, 2, or3 substituents independently selected from fluoro, methyl, hydroxy,hydroxymethyl, cyano, cyanomethyl, methoxy, and C(O)OH.
 16. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ isselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl.
 17. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is selected from H and C₁₋₆ alkyl.
 18. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from H and methyl.
 19. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R^(3′) isselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl.
 20. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R^(3′) is selected from H and C₁₋₆ alkyl.
 21. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(3′) is H.
 22. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from H, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-,CN, NO₂, OR^(a4), and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4A)substituents.
 23. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,4-6 membered heterocycloalkyl, CN, and C(O)OR^(a4), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-6 membered heterocycloalkyl of R⁴ are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4A) substituents; eachR^(a4) and R^(b4) is independently selected from H and C₁₋₆ alkyl. 24.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is selected from H, methyl, ethenyl, isopropenyl, cyano,iodo, cyclopropyl, cyclohexenyl, phenyl, dihydropyridinyl, pyrazolyl,pyrrolyl, and methoxycarbonyl, wherein the methyl, ethenyl, isopropenyl,cyclopropyl, cyclohexenyl, phenyl, dihydropyridinyl, pyrazolyl, andpyrrolyl of R⁴ are each optionally substituted with 1, 2, 3, or 4independently selected R^(4A) substituents.
 25. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein each R^(4A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d4)1, NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41), S(O)R^(b41),S(O)NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, of R^(4A)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents.
 26. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(4A) isindependently selected from halo, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN, OR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)C(O)R^(b41), S(O)₂R^(b41), andS(O)₂NR^(c41)R^(d41), wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl,5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl, of R^(4A)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents.
 27. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: each R^(a41),R^(c41), and R^(d41) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) andR^(d41) are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents; or, any R^(c41) and R^(d41) attached tothe same N atom, together with the N atom to which they are attached,form a 5-10 membered heteroaryl or a 4-10 membered heterocycloalkylgroup, wherein the 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4independently selected R^(4B) substituents; and each R^(b41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,and 4-10 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl of R^(b41) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents.
 28. The compound of claim 1, wherein each R^(4B) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a42), SR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42), OC(O)NR^(c42)R^(d42),NR^(c42)R^(d42) NR^(c42)C(O)R^(b42), and NR^(c42)C(O)OR^(a42), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(4B) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4C)substituents.
 29. The compound of claim 1, wherein: each R^(a42),R^(c42), and R^(d42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and each R^(b42) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl.
 30. The compound of claim 1, wherein each R^(4C) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a43), C(O)R^(b43),C(O)NR^(c43)R^(d43), and C(O)OR^(a43); and each R^(a43), R^(b43),R^(c43), and R^(d43) is independently selected from H and C₁₋₆ alkyl.31. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R^(4A) is independently selected from chloro,fluoro, methyl, hydroxy, methoxy, cyano, C(O)OH, morpholinyl,piperazinyl, cyclopropyl, phenyl, pyrazolyl, C(O)NH₂, C(O)N(CH₃)₂,C(O)NH₂-(cyclopropylmethyl), C(O)NHCH₂CH₃, C(O)NHCH₂CH₂OH, NHC(O)CH₃,SO₂CH₃, SO₂CH₂CH₃, SO₂NHCH₃, SO₂N(CH₃)₂, SO₂-isopropyl, SO₂-cyclopropyl,and SO₂-morpholinyl, wherein the methyl, morpholinyl, piperazinyl,cyclopropyl, phenyl, pyrazolyl, C(O)NH₂-(cyclopropylmethyl),SO₂-isopropyl, SO₂-cyclopropyl, and SO₂-morpholinyl of R^(4A) are eachoptionally substituted with 1 or 2 substituents independently selectedfrom methyl, hydroxy, cyano, dimethylamino, C(O)CH₃, NHC(O)CH₃,C(O)NHCH₃, and CH(CH₃)C(O)NH₂.
 32. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁵ are each optionally substituted with 1, 2, 3, or 4independently selected R^(5A) substituents.
 33. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁵ is selectedfrom H, halo, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, wherein the phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-6 membered heterocycloalkyl of R⁵ are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(5A)substituents.
 34. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from H, halo, and phenylwhich is optionally substituted by 1 or 2 independently selected R^(5A)substituents.
 35. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(5A) is independently selectedfrom C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R^(5A) are each optionally substituted with 1, 2, 3, or 4independently selected R^(5B) substituents.
 36. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein each R^(5A) isindependently selected from phenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the phenyl-C₁₋₆ alkyl-, C₃₋₆cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆ alkyl-, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5B)substituents.
 37. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(5A) is piperidinylmethyl, whichis optionally substituted by 1 or 2 independently selected R^(5B)groups.
 38. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R^(5B) is independently selected fromC(O)R^(b52), C(O)NR^(c52)R^(d52), C(O)OR^(a22) NR^(c52)S(O)R^(b52),R^(c52)S(O)₂R^(b52), S(O)R^(b52), S(O)NR^(c52)R^(d52), S(O)₂R^(b52), andS(O)₂NR^(c52)R^(d52).
 39. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(a52), R^(b52), R^(c52), andR^(d52) is independently selected from H and C₁₋₆ alkyl.
 40. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(5B) is S(O)₂R⁵², wherein each R^(b52) is independentlyselected from H and C₁₋₆ alkyl.
 41. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(5B) ismethylsulfonyl.
 42. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from H, bromo, andphenyl which is optionally substituted by piperidinylmethyl, wherein thepiperidinylmethyl is optionally substituted by methylsulfonyl.
 43. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R¹ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl; R² is selected from H, C₁₋₆ alkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, and (5-10 membered heteroaryl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₆ alkyl-, and (5-10 membered heteroaryl)-C₁₋₆ alkyl- of R²are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; each R^(2A) is independently selected fromhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), andS(O)₂NR^(c21)R^(a21) wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents; R^(a21),R^(b21), R^(c21) and R^(d21) are each independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents; each R^(2B) is independently selected fromhalo, C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22) whereinthe C₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN; each R^(a22), R^(c22), andR^(d22) is independently selected from H and C₁₋₆ alkyl; R³ is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;R^(3′) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl; R⁴ is selected from H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, CN, NO₂, OR^(a4), andC(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R⁴ are each optionally substituted with1, 2, 3, or 4 independently selected R^(4A) substituents; each R^(a4) isindependently selected from H and C₁₋₆ alkyl; each R^(4A) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^(a41),C(O)R^(b41), C(O)NR^(c41)R^(d41), NR^(c41)R^(d41), NR^(c41)C(O)R^(b41),NR^(c41)S(O)R^(b41), NR^(c41)S(O)₂R^(b41), S(O)R^(b41),S(O)NR^(c41)R^(d41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41), wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, of R^(4A)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4B) substituents; each R^(a41), R^(c41), and R^(d41) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a41), R^(c41) and R^(d41) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents; or, any R^(c41) and R^(d41) attached to the same N atom,together with the N atom to which they are attached, form a 5-10membered heteroaryl or a 4-10 membered heterocycloalkyl group, whereinthe 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(4B)substituents; each R^(b41) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10membered heterocycloalkyl of R^(b41) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents; eachR^(4B) is independently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, NO₂, OR^(a42), SR^(a42), C(O)R^(b42),C(O)NR^(c42)R^(d42), C(O)OR^(a42), OC(O)R^(b42), OC(O)NR^(c42)R^(d42),NR^(c42)R^(d42), NR^(c42)C(O)R^(b42), and NR^(c42)C(O)OR^(a42), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(4B) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(4C)substituents; each R^(a42), R^(c42), and R^(d42) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; each R^(b42) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; each R^(4C) is independentlyselected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CN, NO₂, OR^(a43), C(O)R^(b43), C(O)NR^(c43)R^(d43), andC(O)OR^(a43); each R^(a43), R^(b43), R^(c43), and R^(d43) isindependently selected from H and C₁₋₆ alkyl; R⁵ is selected from H,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆alkyl- of R⁵ are each optionally substituted with 1, 2, 3, or 4independently selected R^(5A) substituents; each R^(5A) is independentlyselected from C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-,(5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(5A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(5B) substituents; eachR^(5B) is independently selected from C(O)R^(b22), C(O)NR^(c52)R^(d52),C(O)OR^(a52), NR^(c52)S(O)R^(b52), NR^(c52)S(O)₂R^(b52), S(O)R^(b52),S(O)NR^(c52)R^(d52), S(O)²R^(b52), and S(O)²NR^(c52)R^(d52), and eachR^(a52), R^(b52), R^(c52), and R^(d52) is independently selected from Hand C₁₋₆ alkyl.
 44. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: R¹ is selected from H and C₁₋₆ alkyl;R² is selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆alkyl-, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl-C₁₋₆ alkyl, and (5-6 membered heteroaryl)-C₁₋₆alkyl- of R² are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents; each R^(2A) is independentlyselected from halo, C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-,C(O)NR^(c21)R^(d21), C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21),NR^(c21)R^(d21), NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), whereinthe C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents; R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents; each R^(2B) is independently selected fromhalo, C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), whereinthe C₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN; each R^(a22), R^(c22), andR^(d22) is independently selected from H and C₁₋₆ alkyl; R³ is selectedfrom H and C₁₋₆ alkyl; R^(3′) is selected from H and C₁₋₆ alkyl; R⁴ isselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, CN,and C(O)OR^(a4), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkylof R⁴ are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4A) substituents; each R^(a4) is independently selected fromH and C₁₋₆ alkyl; each R^(4A) is independently selected from halo, C₁₋₆alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, CN, OR^(a41), C(O)R^(b41), C(O)NR^(c41)R^(d41),NR^(c41)C(O)R^(b41), S(O)₂R^(b41), and S(O)₂NR^(c41)R^(d41) wherein theC₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6membered heterocycloalkyl, of R^(4A) are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4B) substituents; eachR^(4B) is independently selected from C₁₋₆ alkyl, CN, OR^(a42),C(O)R^(b42), C(O)NR^(c42)R^(d42), NR^(c42)R^(d42), andNR^(c42)C(O)R^(b42), wherein the C₁₋₆ alkyl of R^(4B) is optionallysubstituted with 1 or 2 independently selected R^(4C) substituents; eachR^(a42), R^(b42), R^(c42), and R^(d42) is independently selected from Hand C₁₋₆ alkyl; each R^(4C) is an independently selectedC(O)NR^(c43)R^(d43) substituent; each R^(c43) and R^(d43) isindependently selected from H and C₁₋₆ alkyl, R⁵ is selected from H,halo, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl, and 4-6 memberedheterocycloalkyl, wherein the phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-6 membered heterocycloalkyl of R⁵ are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5A)substituents; each R^(5A) is independently selected from phenyl-C₁₋₆alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 membered heteroaryl)-C₁₋₆alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein thephenyl-C₁₋₆ alkyl-, C₃₋₆ cycloalkyl-C₁₋₆ alkyl-, (5-6 memberedheteroaryl)-C₁₋₆ alkyl-, and (4-6 membered heterocycloalkyl)-C₁₋₆ alkyl-of R^(5A) are each optionally substituted with 1 or 2 independentlyselected R^(5B) substituents; each R^(5B) is S(O)₂R^(b52); and eachR^(b52) is independently selected from H and C₁₋₆ alkyl.
 45. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R¹ is selected from H and C₁₋₆ alkyl; R² is selected from H,C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl-, and (5-6 membered heteroaryl)-C₁₋₆ alkyl-, whereinthe C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,phenyl-C₁₋₆ alkyl, and (5-6 membered heteroaryl)-C₁₋₆ alkyl- of R² areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; each R^(2A) is independently selected from halo,C₁₋₆ alkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, (4-6membered heterocycloalkyl)-C₁₋₆ alkyl-, C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), and S(O)₂NR^(c21)R^(d21), wherein the C₁₋₆ alkyl,5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (4-6membered heterocycloalkyl)-C₁₋₆ alkyl- of R^(2A) are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2B)substituents; R^(a21), R^(b21), R^(c21), and R^(d21) are eachindependently selected from H, C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl-, (5-10 membered heteroaryl)-C₁₋₆alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₆ alkyl-, wherein theC₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₆alkyl-, (5-10 membered heteroaryl)-C₁₋₆ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₆ alkyl- of R^(a21), R^(b21), R^(c21), and R^(d21)are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents; each R^(2B) is independently selected fromhalo, C₁₋₆ alkyl, CN, OR^(a22), C(O)OR^(a22), NR^(c22)R^(d22), whereinthe C₁₋₆ alkyl is optionally substituted with 1 or 2 R^(2C) substituentsindependently selected from OH and CN; each R^(a22), R^(c22), andR^(d22) is independently selected from H and C₁₋₆ alkyl; R³ is selectedfrom H and C₁₋₆ alkyl; R^(3′) is H; R⁴ is selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,4-6 membered heterocycloalkyl, CN, and C(O)OR^(a4), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-6 membered heterocycloalkyl of R⁴ are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(4A) substituents; eachR^(a4) is independently selected from H and C₁₋₆ alkyl; each R^(4A) isindependently selected from chloro, fluoro, methyl, hydroxy, methoxy,cyano, C(O)OH, morpholinyl, piperazinyl, cyclopropyl, phenyl, pyrazolyl,C(O)NH₂, C(O)N(CH₃)₂, C(O)NH₂-(cyclopropylmethyl), C(O)NHCH₂CH₃,C(O)NHCH₂CH₂OH, NHC(O)CH₃, SO₂CH₃, SO₂CH₂CH₃, SO₂NHCH₃, SO₂N(CH₃)₂,SO₂-isopropyl, SO₂-cyclopropyl, and SO₂-morpholinyl, wherein the methyl,morpholinyl, piperazinyl, cyclopropyl, phenyl, pyrazolyl,C(O)NH₂-(cyclopropylmethyl), SO₂-isopropyl, SO₂-cyclopropyl, andSO₂-morpholinyl of R^(4A) are each optionally substituted with 1 or 2substituents independently selected from methyl, hydroxy, cyano,dimethylamino, C(O)CH₃, NHC(O)CH₃, C(O)NHCH₃, and CH(CH₃)C(O)NH₂; R⁵ isselected from H, halo, and phenyl which is optionally substituted by 1or 2 independently selected R^(5A) substituents; each R^(5A) ispiperidinylmethyl, which is optionally substituted by 1 or 2independently selected R^(5B) groups; each R^(5B) is S(O)₂R^(b52); andeach R^(b52) is independently selected from H and C₁₋₆ alkyl.
 46. Thecompound of claim 1, wherein the compound of Formula I is a compound ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,or
 4. 47. The compound of claim 1, wherein the compound of Formula I isa compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or
 4. 48. The compound of claim 1, wherein the compound of Formula I isa compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3,or
 4. 49. The compound of claim 1, wherein the compound of Formula I isa compound of Formula V:

or a pharmaceutically acceptable salt thereof.
 50. The compound of claim1, wherein the compound of Formula I is a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3,or 4; and p is 0, 1, 2, 3, or
 4. 51. The compound of claim 1, whereinthe compound of Formula I is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4; and p is 0, 1, 2, 3, or
 4. 52. The compound of claim 1, which isselected from:4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-phenyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-(pyridin-3-ylmethyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;2-cyclohexyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)cyclohexane-1-carboxylicacid;4-(8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)piperidine-1-sulfonamide;2-(4-((2-methoxyethyl)amino)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;2-cyano-N-(4-(4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)phenyl)acetamide;4-(1,4-dimethyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-(pyridin-3-yl)benzamide;4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)-N-methylbenzamide;N-(2-(2-benzylhydrazineyl)-2-oxoethyl)-4-(9-(4-methoxyphenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzamide;4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-((1-cyanocyclopropyl)methyl)benzamide;4-(9-(methoxycarbonyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;N-(4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)benzyl)acetamide;4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)-N-methylbenzenesulfonamide;9-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-3-one;2-(4-(4-(2-(tert-butyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-9-yl)phenyl)-1H-pyrazol-1-yl)propanamide;4-(9-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;4-(9-(4-(1-aminocyclopropyl)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;4-(4-methyl-9-(1-methyl-1H-pyrrol-3-yl)-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;4-(9-cyclopropyl-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid;4-(9-cyano-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid; and4-(9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid; or a pharmaceutically acceptable salt thereof.
 53. The compound ofclaim 1, which is4-(8-cyclopropyl-9-(4-methoxyphenyl)-4-methyl-3-oxo-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[3,4-d]pyrimidin-2-yl)benzoicacid, or a pharmaceutically acceptable salt thereof.
 54. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound is deuterated.
 55. A pharmaceutical composition, comprising acompound of claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 56. A method of inhibiting anactivity of the V617F variant of JAK2 kinase, comprising contacting thekinase with a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 57. A method of treating cancer in a patient in need thereof,the method comprising administering to the patient a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 58. The method of claim 57, wherein the canceris selected from bladder cancer, breast cancer, cervical cancer,colorectal cancer, cancer of the small intestine, colon cancer, rectalcancer, cancer of the anus, endometrial cancer, gastric cancer, head andneck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer,prostate cancer, testicular cancer, uterine cancer, vulvar cancer,esophageal cancer, gall bladder cancer, pancreatic cancer, stomachcancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skincancer, and brain cancer.
 59. The method of claim 57, wherein the canceris a hematological cancer.
 60. The method of claim 57, wherein thecancer is selected from leukemia, lymphoma, multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia,B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia,Hodgkin's or non-Hodgkin's lymphoma, a myeloproliferative neoplasm),myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma,acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt'slymphoma.
 61. A method of treating a myeloproliferative disorder in apatient in need thereof, the method comprising administering to thepatient a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof.
 62. The method of claim 61,wherein the myeloproliferative disorder is selected from polycythemiavera, essential thrombocythemia, myelofibrosis with myeloid metaplasia,primary myelofibrosis, post- essential thrombocythemia myelofibrosis,post polycythemia vera myelofibrosis, chronic myelogenous leukemia,chronic myelomonocytic leukemia, hypereosinophilic syndrome, andsystemic mast cell disease.
 63. A method of treating myelodysplasticsyndrome in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.